Benzimidazol derivatives for treating filovirus infection

ABSTRACT

The present invention relates to compounds comprising a benzimidazole scaffold, and the use of such compounds for the treatment of viral diseases. The invention also relates to pharmaceutical compositions comprising said compounds as an active ingredient. In particular the compounds of the invention comprising a benzimidazole scaffold are used for the treatment of filoviruses or retroviruses, and preferably for the treatment of Ebola virus or HIV virus.

The present invention relates to compounds comprising a benzimidazolescaffold, and the use of such compounds for the treatment of viraldiseases. The invention also relates to pharmaceutical compositionscomprising said compounds as active ingredient.

In particular the compounds of the invention comprising a benzimidazolescaffold are used for the treatment of filoviruses or retroviruses, andpreferably for the treatment of Ebola virus or HIV virus.

Viruses can infect all types of life forms, from bacteria to humanbeings. In humans, problems appear when the immune system cannot destroythe virus, and it brings a disease. There is a large number ofidentified viruses, being pathogenic for humans. Depending on the typeof virus they can easily and rapidly spread through organisms and causea problem of public health. Some of them are difficult to control andover the years of human history they caused epidemics with manyfatalities as the Spanish flu in 1918 with about 30 million deaths,polio in the 30s, the herpes virus in the 60s, AIDS since the 80s, andmore recently Ebola virus. Until the 1960s the strategy to fight viralinfections was largely based on vaccination. However over the last fiftyyears the researchers focused on developing small molecules whichselectively interfere with one or more biological processesparticipating in virus life cycle.

Thus, there is a need to develop new molecules to interfere with virusesand fight against viral diseases. Indeed, for filoviruses for instance,the unpredictable onset, simplicity of transmission, fast progression ofdisease, high fatality make difficult to produce an efficient treatment.Thus, the developing of specific treatment is necessary. Specifically,the developing of specific treatment for disease linked to filovirusesis necessary.

Ebola virus is a RNA-virus belonging to the filovirus family. Differentways to fight the virus are known and possible, such as blocking thevirus at the entry of the host cell or blocking the replication of thevirus as well as host immune responses. To date, there is no vaccineavailable or approved antiviral for use against Ebola virus.Nevertheless, new compounds are widely studied. In particular, moleculeshave been synthesized aiming to inhibit Ebola virus blocking its entryinto the host cell.

Côté et al. identified a benzylpiperazine adamantane-derived compound aseffective inhibitor of Ebola virus entry (Côté, M.; Misasi, J. Smallmolecule inhibitors reveal NPC1 is essential for Ebola virus infection.Nature 2011, 477, 344-348). However, these compounds have somelimitations; the most important limiting pharmacokinetic parameter isthe short biological half-life.

Basu et al. reported that the benzodiazepine derivatives are specificinhibitors of EBOV entry (Basu, A.; Li, B., Identification of asmall-molecule entry inhibitor for Filoviruses. J. Virol. 2011, 85,3106-3119). However, these molecules are very specific to Ebola virusand present a very weak activity against other viruses.

Thus, there is a need to develop new molecules especially showing anEbola virus inhibition activity, but also an inhibition against otherfiloviruses, or retroviruses, or other diseases or pathologies.

The present invention relates to a compound of formula (I)

in which:

-   -   X represents:        -   a C═O group;        -   an alkyl group, linear or branched, comprising 1 to 6 carbon            atoms; or        -   a group of formula —NR—(C₁-C₆)alkyl-, the alkyl being linear            or branched;    -   Y represents CH or nitrogen atom;    -   R¹ represents:        -   an aryl group, comprising 6 to 10 carbon atoms,            non-substituted or substituted by at least one group chosen            among: haloalkyl, haloalkoxyl, alkyl or alkoxyl group, the            alkyl being linear or branched, and comprising 1 to 6 carbon            atoms;        -   an heteroaryl group, comprising 5 to 10 members,            non-substituted or substituted by at least one group chosen            among: haloalkyl, haloalkoxyl, alkyl or alkoxyl group, the            alkyl being linear or branched, and comprising 1 to 6 carbon            atoms;        -   a CH-(aryl)₂ group, the aryl comprising 6 to 10 carbon            atoms, non-substituted or substituted by at least one group            chosen among: haloalkyl, haloalkoxyl, alkyl or alkoxyl            group, the alkyl being linear or branched, and comprising 1            to 6 carbon atoms; or        -   a CH-(heteroaryl)₂ group, the heteroaryl comprising 5 to 10            members, non-substituted or substituted by at least one            group chosen among: haloalkyl, haloalkoxyl, alkyl or alkoxyl            group, the alkyl being linear or branched, and comprising 1            to 6 carbon atoms;    -   R² represents:        -   a (C₁-C₆)alkyl-aryl-R³ group, the aryl comprising 6 to 10            carbon atoms and the alkyl being linear or branched;        -   a C(O)N(R)-aryl-R⁵ group, the aryl comprising between 6 to            10 carbon atoms;        -   a C(O)—(C₁-C₆)alkyl-O-aryl-Hal group, with Hal represents an            halogen, the aryl comprising between 6 and 10 carbon atoms            and the alkyl being linear or branched;        -   a C(O)O—(C₁-C₆)alkyl-aryl group, the aryl comprising between            6 to 10 carbon atoms and the alkyl being linear or branched;            or        -   a O-aryl-R³ group, the aryl comprising between 6 to 10            carbon atoms;    -   R³ represents a OR⁴ group, haloalkyl or haloakoxyl, wherein the        alkyl is linear or branched, and comprises 1 to 6 carbon atoms;    -   R⁴ represents a (C₁-C₆)alkyl-aryl-COOR group, a haloalkyl group        or a (C₁-C₆)alkyl-aryl-(C₁-C₆)alkyl-PO(OR)₂ group, wherein alkyl        is linear or branched and comprises 1 to 6 carbon atoms and the        aryl comprises between 6 and 10 carbon atoms;    -   R⁵ represents an alkyl group, linear or branched, comprising 1        to 6 carbon atoms; or a haloalkyl, linear or branched,        comprising 1 to 6 carbon atoms;    -   R represents an alkyl group, linear or branched, comprising 1 to        6 carbon atoms, or a hydrogen atom;        or their pharmaceutically acceptable salts, hydrates, solvates,        esters or their optical isomers, racemates, diastereoisomers,        enantiomers, tautomers, or a mixture thereof.

In one embodiment, the present invention relates to a compound offormula (I) in which:

-   -   X represents:        -   a C═O group;        -   an alkyl group, linear or branched, comprising 1 to 6 carbon            atoms; or        -   a group of formula —NR—(C₁-C₆)alkyl-, the alkyl being linear            or branched;    -   Y represents CH or nitrogen atom;    -   R¹ represents:        -   an aryl group, comprising 6 to 10 carbon atoms,            non-substituted or substituted by at least one group chosen            among: haloalkyl, haloalkoxyl, alkyl or alkoxyl group, the            alkyl being linear or branched, and comprising 1 to 6 carbon            atoms;        -   an heteroaryl group, comprising 5 to 10 members,            non-substituted or substituted by at least one group chosen            among: haloalkyl, haloalkoxyl, alkyl or alkoxyl group, the            alkyl being linear or branched, and comprising 1 to 6 carbon            atoms;        -   a CH-(aryl)₂ group, the aryl comprising 6 to 10 carbon            atoms, non-substituted or substituted by at least one group            chosen among: haloalkyl, haloalkoxyl, alkyl or alkoxyl            group, the alkyl being linear or branched, and comprising 1            to 6 carbon atoms; or        -   a CH-(heteroaryl)₂ group, the heteroaryl comprising 5 to 10            members, non-substituted or substituted by at least one            group chosen among: haloalkyl, haloalkoxyl, alkyl or alkoxyl            group, the alkyl being linear or branched, and comprising 1            to 6 carbon atoms;    -   R² represents:        -   a (C₁-C₆)alkyl-aryl-R³ group, the aryl comprising 6 to 10            carbon atoms and the alkyl being linear or branched;        -   a C(O)N(R)-aryl-R⁵ group, the aryl comprising between 6 to            10 carbon atoms; or        -   a C(O)—(C₁-C₆)alkyl-O-aryl-Hal group, with Hal represents an            halogen, the aryl comprising between 6 and 10 carbon atoms            and the alkyl being linear or branched;    -   R³ represents a OR⁴ group, haloalkyl or haloakoxyl, wherein the        alkyl is linear or branched, and comprises 1 to 6 carbon atoms;    -   R⁴ represents a (C₁-C₆)alkyl-aryl-COOR group, a haloalkyl group        or a (C₁-C₆)alkyl-aryl-(C₁-C₆)alkyl-PO(OR)₂ group, wherein alkyl        is linear or branched and comprises 1 to 6 carbon atoms and the        aryl comprises between 6 and 10 carbon atoms;    -   R⁵ represents an alkyl group, linear or branched, comprising 1        to 6 carbon atoms; or a haloalkyl, linear or branched,        comprising 1 to 6 carbon atoms;    -   R represents an alkyl group, linear or branched, comprising 1 to        6 carbon atoms, or a hydrogen atom;        or their pharmaceutically acceptable salts, hydrates, solvates,        esters or their optical isomers, racemates, diastereoisomers,        enantiomers, tautomers, or a mixture thereof.        Preferably, in the compound of formula (I), R¹ is chosen among:    -   a phenyl group, non-substituted or substituted by at least one        group chosen among: haloalkyl, haloalkoxyl, alkyl or alkoxyl        group, the alkyl being linear or branched, and comprising 1 to 6        carbon atoms;    -   a pyridine group non-substituted or substituted by at least one        group chosen among: haloalkyl, haloalkoxyl, alkyl or alkoxyl        group, the alkyl being linear or branched, and comprising 1 to 6        carbon atoms;    -   a pyrimidine group, non-substituted or substituted by at least        one group chosen among: haloalkyl, haloalkoxyl, alkyl or alkoxyl        group, the alkyl being linear or branched, and comprising 1 to 6        carbon atoms; or    -   a benzhydryl group non-substituted or substituted by at least        one group chosen among: haloalkyl, haloalkoxyl, alkyl or alkoxyl        group, the alkyl being linear or branched, and comprising 1 to 6        carbon atoms.        Preferably, in the compound of formula (I), R¹ is chosen among:    -   a phenyl group non-substituted or substituted by at least one        group chosen among: fluoroalkyl, fluoroalkoxyl, alkyl or alcoxyl        group, the alkyl being linear or branched, and comprising 1 to 6        carbon atoms;    -   a pyridine group non-substituted or substituted by at least one        group chosen among: haloalkyl, haloalkoxyl, alkyl or alkoxyl        group, the alkyl being linear or branched, and comprising 1 to 6        carbon atoms; or    -   a benzhydryl group non-substituted or substituted by at least        one group chosen among: fluoroalkyl, fluoroalkoxyl, alkyl or        alcoxyl group, the alkyl being linear or branched, and        comprising 1 to 6 carbon atoms.

Preferably, in the compound of formula (I), X represents:

-   -   a (C═O) group; or    -   an alkyl group, linear or branched, comprising 1 to 3 carbon        atoms.        Preferably, in the compound of formula (I), Y represents a CH        group. In another preferred embodiment of the invention, Y        preferably represents a nitrogen atom.        Preferably, in the compound of formula (I), R¹ is chosen among:    -   a phenyl group, non-substituted or substituted by at least one        group chosen among: haloalkyl, haloalkoxyl, alkyl or alkoxyl        group, the alkyl being linear or branched, and comprising 1 to 6        carbon atoms;    -   a pyridine group non-substituted or substituted by at least one        group chosen among: haloalkyl, haloalkoxyl, alkyl or alkoxyl        group, the alkyl being linear or branched, and comprising 1 to 6        carbon atoms;    -   a pyrimidine group, non-substituted or substituted by at least        one group chosen among: haloalkyl, haloalkoxyl, alkyl or alkoxyl        group, the alkyl being linear or branched, and comprising 1 to 6        carbon atoms; or    -   a benzhydryl group non-substituted or substituted by at least        one group chosen among: haloalkyl, haloalkoxyl, alkyl or alkoxyl        group, the alkyl being linear or branched, and comprising 1 to 6        carbon atoms;        and X represents:    -   a (C═O) group; or    -   an alkyl group, linear or branched, comprising 1 to 3 carbon        atoms.        Preferably, in the compound of formula (I), R¹ is chosen among:    -   a phenyl group, non-substituted or substituted by at least one        group chosen among: haloalkyl, haloalkoxyl, alkyl or alkoxyl        group, the alkyl being linear or branched, and comprising 1 to 6        carbon atoms;    -   a pyridine group non-substituted or substituted by at least one        group chosen among: haloalkyl, haloalkoxyl, alkyl or alkoxyl        group, the alkyl being linear or branched, and comprising 1 to 6        carbon atoms;    -   a pyrimidine group, non-substituted or substituted by at least        one group chosen among: haloalkyl, haloalkoxyl, alkyl or alkoxyl        group, the alkyl being linear or branched, and comprising 1 to 6        carbon atoms; or    -   a benzhydryl group non-substituted or substituted by at least        one group chosen among: haloalkyl, haloalkoxyl, alkyl or alkoxyl        group, the alkyl being linear or branched, and comprising 1 to 6        carbon atoms;    -   and Y represents a CH group.        Preferably, in the compound of formula (I), R¹ is chosen among:    -   a phenyl group, non-substituted or substituted by at least one        group chosen among: haloalkyl, haloalkoxyl, alkyl or alkoxyl        group, the alkyl being linear or branched, and comprising 1 to 6        carbon atoms;    -   a pyridine group non-substituted or substituted by at least one        group chosen among: haloalkyl, haloalkoxyl, alkyl or alkoxyl        group, the alkyl being linear or branched, and comprising 1 to 6        carbon atoms;    -   a pyrimidine group, non-substituted or substituted by at least        one group chosen among: haloalkyl, haloalkoxyl, alkyl or alkoxyl        group, the alkyl being linear or branched, and comprising 1 to 6        carbon atoms; or    -   a benzhydryl group non-substituted or substituted by at least        one group chosen among: haloalkyl, haloalkoxyl, alkyl or alkoxyl        group, the alkyl being linear or branched, and comprising 1 to 6        carbon atoms;        and Y represents a nitrogen atom.        Preferably, in the compound of formula (I), X represents:    -   a (C═O) group; or    -   an alkyl group, linear or branched, comprising 1 to 3 carbon        atoms;        and Y represents a CH group.        Preferably, in the compound of formula (I), X represents:    -   a (C═O) group; or    -   an alkyl group, linear or branched, comprising 1 to 3 carbon        atoms;    -   and Y represents a nitrogen atom.        Preferably, in the compound of formula (I), R¹ is chosen among:    -   a phenyl group, non-substituted or substituted by at least one        group chosen among: haloalkyl, haloalkoxyl, alkyl or alkoxyl        group, the alkyl being linear or branched, and comprising 1 to 6        carbon atoms;    -   a pyridine group non-substituted or substituted by at least one        group chosen among: haloalkyl, haloalkoxyl, alkyl or alkoxyl        group, the alkyl being linear or branched, and comprising 1 to 6        carbon atoms;    -   a pyrimidine group, non-substituted or substituted by at least        one group chosen among: haloalkyl, haloalkoxyl, alkyl or alkoxyl        group, the alkyl being linear or branched, and comprising 1 to 6        carbon atoms; or    -   a benzhydryl group non-substituted or substituted by at least        one group chosen among: haloalkyl, haloalkoxyl, alkyl or alkoxyl        group, the alkyl being linear or branched, and comprising 1 to 6        carbon atoms.        and X represents:    -   a (C═O) group; or    -   an alkyl group, linear or branched, comprising 1 to 3 carbon        atoms;    -   and Y represents a CH group.        Preferably, in the compound of formula (I), R¹ is chosen among:    -   a phenyl group, non-substituted or substituted by at least one        group chosen among: haloalkyl, haloalkoxyl, alkyl or alkoxyl        group, the alkyl being linear or branched, and comprising 1 to 6        carbon atoms;    -   a pyridine group non-substituted or substituted by at least one        group chosen among: haloalkyl, haloalkoxyl, alkyl or alkoxyl        group, the alkyl being linear or branched, and comprising 1 to 6        carbon atoms;    -   a pyrimidine group, non-substituted or substituted by at least        one group chosen among: haloalkyl, haloalkoxyl, alkyl or alkoxyl        group, the alkyl being linear or branched, and comprising 1 to 6        carbon atoms; or    -   a benzhydryl group non-substituted or substituted by at least        one group chosen among: haloalkyl, haloalkoxyl, alkyl or alkoxyl        group, the alkyl being linear or branched, and comprising 1 to 6        carbon atoms.        and X represents:    -   a (C═O) group; or    -   an alkyl group, linear or branched, comprising 1 to 3 carbon        atoms;        and Y represents a nitrogen group.

As used hereabove or hereafter:

“Alkyl” means an aliphatic hydrocarbon group which may be straight orbranched having 1 to 6 carbon atoms in the chain. “Branched” means thatone or more lower alkyl groups such as methyl, ethyl or propyl areattached to a linear alkyl chain. Exemplary alkyl groups include methyl,ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, 3-pentyl.

“Alkoxyl” means an O-alkyl group, the alkyl group being as describedabove.

“Alken” or “alkenyl” means an aliphatic hydrocarbon group containing acarbon-carbon double bond and which may be straight or branched having 2to 6 carbon atoms in the chain. Preferred alkenyl groups have 2 to 6carbon atoms in the chain; and more preferably about 2 to 4 carbon atomsin the chain. Exemplary alkenyl groups include ethenyl, propenyl,n-butenyl, i-butenyl, 3-methylbut-2-enyl, n-pentenyl.

“Aryl” means an aromatic monocyclic or multicyclic hydrocarbon ringsystem of 6 to 14 carbon atoms, preferably of 6 to 10 carbon atoms,substituted or not. Exemplary aryl groups include phenyl or naphthyl.

“Halogen atom” refers to fluorine, chlorine, bromine or iodine atom;preferably fluorine atom.

“Haloalkyl” refers to an alkyl group as described above substituted byat least one halogen atom as described above, for example substituted by1 to 6 halogen atoms, preferably by 1 to 3 halogen atoms. Exemplaryhaloalkyl group includes trifluoromethyl group.

“Haloalkoxyl” refers to an alkoxyl group as described above substitutedby at least one halogen atom as described above, for example substitutedby 1 to 6 halogen atoms, preferably by 1 to 3 halogen atoms, for example—OCF₃.

As used herein, the term “heteroaryl” refers to a 5 to 14, preferably 5to 10-membered aromatic hetero, mono-, bi- or multicyclic ringcomprising at least one heteroatom preferably chosen among: O, N or S,preferably from 1 to 5 heteroatoms, for example from 1 to 4 heteroatoms,especially one, two or three heteroatoms. Examples include pyrrolyl,pyridyl, pyrazolyl, thienyl, pyrimidinyl, pyrazinyl, tetrazolyl,indolyl, quinolinyl, purinyl, imidazolyl, thienyl, thiazolyl,benzothiazolyl, furanyl, benzofuranyl, 1,2,4-thiadiazolyl, isothiazolyl,triazoyl, tetrazolyl, isoquinolyl, benzothienyl, isobenzofuryl,pyrazolyl, carbazolyl, benzimidazolyl, isoxazolyl, pyridyl-N-oxide, aswell as the fused systems resulting from the condensation with a phenylgroup.

“Alkyl”, “aryl”, “alkoxyl”, “haloalkoxyl”, “haloalkyl”, “heteroaryl” andthe likes refers also to the corresponding “alkylene”, “arylene”,“alkoxylene”, “haloalkoxylene”, “haloalkylene” “heteroarylene” and thelikes which are formed by the removal of two hydrogen atoms. Alkyl andalkylene are used herein interchangeably.

As used herein, the expression “pharmaceutically acceptable” refers tothose compounds, materials, excipients, compositions or dosage formswhich are, within the scope of sound medical judgment, suitable forcontact with the tissues of human beings and animals without excessivetoxicity, irritation, allergic response or other problem complicationscommensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. The pharmaceutically acceptable saltsinclude the conventional non-toxic salts or the quaternary ammoniumsalts of the parent compound formed, for example, from non-toxicinorganic or organic acids. For example, such conventional non-toxicsalts include those derived from inorganic acids such as hydrochloric,hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like,including mono, di or tri-salts thereof; and the salts prepared fromorganic acids such as acetic, propionic, succinic, tartaric, citric,methanesulfonic, benzenesulfonic, glucoronic, glutamic, benzoic,salicylic, toluenesulfonic, oxalic, fumaric, maleic, lactic and thelike. Further addition salts include ammonium salts such astromethamine, meglumine, epolamine, etc., metal salts such as sodium,potassium, calcium, zinc or magnesium.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two. Generally, non-aqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 20^(th) ed., Mack Publishing Company, Easton,Pa., 2000, the disclosure of which is hereby incorporated by reference.

The compounds of the general formula (I) having geometrical andstereoisomers are also a part of the invention.

The compounds of the present invention may be prepared in a number ofways well-known to those skilled in the art. The compounds can besynthesized, for example, by application or adaptation of the methodsknown by the skilled person. The appropriate modifications andsubstitutions will be readily apparent and well known or readilyobtainable from the scientific literature to those skilled in the art.

It will be appreciated that the compounds of the present invention maycontain one or more asymmetrically substituted carbon atoms, and may beisolated in optically active or racemic forms. Thus, all chiral,diastereomeric, racemic forms, isomeric forms of a structure areintended, unless the specific stereochemistry or isomeric form isspecifically indicated. It is well-known in the art how to prepare andisolate such optically active forms. For example, mixtures ofstereoisomers may be separated by standard techniques including, but notlimited to, resolution of racemic forms, normal, reverse-phase, andchiral chromatography, preferential salt formation, recrystallization,and the like, or by chiral synthesis either from chiral startingmaterials or by deliberate synthesis of target chiral centers.

Compounds of the present invention may be prepared by a variety ofsynthetic routes as shown in the examples, which can be adapted by theskilled person based on its knowledge with regards to the desiredcompounds.

The present invention also relates to pharmaceutical compositionscomprising at least one compound of formula (I) as active principle.Preferably, the present invention also relates to pharmaceuticalcompositions comprising at least one compound of formula (I) as activeprinciple and at least one excipient pharmaceutically acceptable.

According to the invention, the terms “patient” or “patient in needthereof”, are intended for an animal such as a valuable animal forbreeding, company or preservation purposes, or a human or a human child,being affected or likely to be affected with one or more diseases andconditions described herein. Preferably, the patient is human.

The identification of those subjects who are in need of treatment ofherein-described diseases and conditions is well within the ability andknowledge of one skilled in the art. A veterinarian or a physicianskilled in the art can readily identify, by the use of clinical tests,physical examination, medical/family history or biological anddiagnostic tests, those subjects who are in need of such treatment.

As used herein, a “therapeutically effective amount” refers to an amountof a compound of the present invention which is effective in preventing,reducing, eliminating, treating or controlling the symptoms of theherein-described diseases and conditions. The term “controlling” isintended to refer to all processes wherein there may be a slowing,interrupting, arresting, or stopping of the progression of the diseasesand conditions described herein, but does not necessarily indicate atotal elimination of all disease and condition symptoms, and is intendedto include prophylactic treatment.

A therapeutically effective amount can be readily determined by theattending diagnostician, as one skilled in the art, by the use ofconventional techniques and by observing results obtained underanalogous circumstances. In determining the therapeutically effectiveamount, a number of factors are considered by the attendingdiagnostician, including, but not limited to: the species of subject;its size, age, and general health; the specific disease involved; thedegree of involvement or the severity of the disease; the response ofthe individual subject; the particular compound administered; the modeof administration; the bioavailability characteristic of the preparationadministered; the dose regimen selected; the use of concomitantmedication; and other relevant circumstances.

The amount of a compound of formula (I), which is required to achievethe desired biological effect, will vary depending upon a number offactors, including the chemical characteristics of the compoundsemployed, the potency of the compounds, the type of disease, the speciesto which the patient belongs, the diseased state of the patient, theroute of administration, the bioavailability of the compound by thechosen route, all factors which dictate the required dose amounts,delivery and regimen to be administered.

As used herein, “pharmaceutically acceptable excipient” includes anycarriers, diluents, adjuvants, or vehicles, such as preserving orantioxidant agents, fillers, disintegrating agents, wetting agents,emulsifying agents, suspending agents, solvents, dispersion media,coatings, antibacterial and antifungal agents, isotonic and absorptiondelaying agents and the like. The use of such media and agents forpharmaceutical active substances is well-known in the art. Exceptinsofar as any conventional media or agent is incompatible with theactive ingredient, its use in the therapeutic compositions iscontemplated. Supplementary active ingredients can also be incorporatedinto the compositions as suitable therapeutic combinations.

In the context of the invention, the term “treating” or “treatment”, asused herein, means reversing, alleviating, inhibiting the progress of,or preventing the disorder or condition to which such term applies, orone or more symptoms of such disorder or condition.

The preferred dosage of drug to be administered is likely to depend onsuch variables as the type and extent of progression of the disease ordisorder, the overall health status of the particular patient, therelative biological efficacy of the compound selected, the formulationof the compound, the route of administration (intravenous,intramuscular, or other), the pharmacokinetic properties of the compoundby the chosen delivery route, and the speed (bolus or continuousinfusion) and schedule of administrations (number of repetitions in agiven period of time).

The compound of formula (I) of the present invention is also capable ofbeing administered in unit dose forms, wherein the expression “unitdose” means a single dose which is capable of being administered to apatient, and which can be readily handled and packaged, remaining as aphysically and chemically stable unit dose comprising either the activecompound itself, or as a pharmaceutically acceptable composition, asdescribed hereinafter. Compounds provided herein can be formulated intopharmaceutical compositions by admixture with one or morepharmaceutically acceptable excipients. Such unit dose compositions maybe prepared for use by oral administration, particularly in the form oftablets, simple capsules or soft gel capsules; or intranasally,particularly in the form of powders, nasal drops, or aerosols; ordermally, for example, topically in ointments, creams, lotions, gels orsprays, or via trans-dermal patches.

The compositions may conveniently be administered in unit dosage formand may be prepared by any of the methods well-known in thepharmaceutical art.

For oral administration, tablets, pills, powders, capsules, troches andthe like can contain one or more of any of the following ingredients, orcompounds of a similar nature: a binder such as microcrystallinecellulose, or gum tragacanth; a diluent such as starch or lactose; adisintegrant such as starch and cellulose derivatives; a lubricant suchas magnesium stearate; a glidant such as colloidal silicon dioxide; asweetening agent such as sucrose or saccharin; or a flavoring agent suchas peppermint, or methyl salicylate. Capsules can be in the form of ahard capsule or soft capsule, which are generally made from gelatinblends optionally blended with plasticizers, as well as a starchcapsule. In addition, dosage unit forms can contain various othermaterials that modify the physical form of the dosage unit, for example,coatings of sugar, shellac, or enteric agents. Other oral dosage formssyrup or elixir may contain sweetening agents, preservatives, dyes,colorings, and flavorings. In addition, the active compounds may beincorporated into fast dissolved, modified-release or sustained-releasepreparations and formulations, and wherein such sustained-releaseformulations are preferably bi-modal. Preferred tablets contain lactose,cornstarch, magnesium silicate, croscarmellose sodium, povidone,magnesium stearate, or talc in any combination.

Liquid preparations for parenteral administration include sterileaqueous or non-aqueous solutions, suspensions, and emulsions. The liquidcompositions may also include binders, buffers, preservatives, chelatingagents, sweetening, flavoring and coloring agents, and the like.Non-aqueous solvents include alcohols, propylene glycol, polyethyleneglycol, vegetable oils such as olive oil, and organic esters such asethyl oleate. Aqueous carriers include mixtures of alcohols and water,buffered media, and saline. In particular, biocompatible, biodegradablelactide polymer, lactide/glycolide copolymer, orpolyoxyethylene-polyoxypropylene copolymers may be useful excipients tocontrol the release of the active compounds. Intravenous vehicles caninclude fluid and nutrient replenishers, electrolyte replenishers, suchas those based on Ringer's dextrose, and the like. Other potentiallyuseful parenteral delivery systems for these active compounds includeethylene-vinyl acetate copolymer particles, osmotic pumps, implantableinfusion systems, and liposomes.

Alternative modes of administration include formulations for inhalation,which include such means as dry powder, aerosol, or drops. They may beaqueous solutions containing, for example, polyoxyethylene-9-laurylether, glycocholate and deoxycholate, or oily solutions foradministration in the form of nasal drops, or as a gel to be appliedintranasally. Formulations for buccal administration include, forexample, lozenges or pastilles and may also include a flavored base,such as sucrose or acacia, and other excipients such as glycocholate.Formulations suitable for rectal administration are preferably presentedas unit-dose suppositories, with a solid based carrier, and may includea salicylate. Formulations for topical application to the skinpreferably take the form of an ointment, cream, lotion, paste, gel,spray, aerosol, or oil. Carriers which can be used include petroleumjelly, lanolin, polyethylene glycols, alcohols, or their combinations.Formulations suitable for transdermal administration can be presented asdiscrete patches and can be lipophilic emulsions or buffered, aqueoussolutions, dissolved and/or dispersed in a polymer or an adhesive.

The present invention also relates to at least one compound of formula(I) of the invention, or to the composition of the invention for use forthe treatment of viral diseases.

In the present invention “compound X for the treatment of Y” isequivalent to “compound X for use in a method for the treatment of Y” or“compound X for use in the therapy of Y”.

The present invention also relates to the use of at least one compoundof formula (I) of the invention or of the composition of the inventionfor the preparation of a medicine for the treatment of viral diseases.

The present invention also relates to a method of treatment of viraldiseases comprising the administration of a therapeutically effectiveamount of at least one compound of formula (I) of the invention or ofthe composition of the invention to a patient in need thereof.

The present invention also relates to at least one compound of formula(I) of the invention or to the composition of the invention for use forthe treatment of infections with a filovirus. Preferably, the inventionrelates to at least one compound of formula (I) of the invention or tothe composition of the invention for use for the treatment of infectionswith Ebola virus.

The present invention also relates to the use of at least one compoundof formula (I) of the invention or of the composition of the inventionfor the preparation of a medicine for the treatment of infections withfilovirus. Preferably, the invention relates to the use of at least onecompound of formula (I) of the invention or of the composition of theinvention for the preparation of a medicine for the treatment ofinfections with Ebola virus.

The present invention also relates to a method of treatment ofinfections with a filovirus comprising the administration of atherapeutically effective amount of at least one compound of formula (I)of the invention or of the composition of the invention to a patient inthe need thereof. Preferably, the invention relates to a method oftreatment of infections with Ebola virus comprising the administrationof a therapeutically effective amount of at least one compound offormula (I) of the invention or of the composition of the invention to apatient in the need thereof.

The present invention also relates to at least one compound of formula(I) of the invention for use for the treatment of infections with aretrovirus. Preferably, the invention relates to at least one compoundof formula (I) of the invention or of the composition of the inventionfor use for the treatment of infections with Human ImmunodeficiencyVirus (HIV).

The present invention also relates to the use of at least one compoundof formula (I) of the invention or of the composition of the inventionfor the preparation of a medicine for the treatment of infections with aretrovirus. Preferably, the invention relates to the use of at least onecompound of formula (I) of the invention or of the composition of theinvention for the preparation of a medicine the treatment of infectionswith Human Immunodeficiency Virus (HIV).

The present invention also relates to a method of treatment ofinfections with a retrovirus comprising the administration of atherapeutically effective amount of at least one compound of formula (I)of the invention or of the composition of the invention to a patient inthe need thereof. Preferably, the invention relates to a method oftreatment of infections with Human Immunodeficiency Virus (HIV)comprising the administration of a therapeutically effective amount ofat least one compound of formula (I) of the invention or of thecomposition of the invention to a patient in the need thereof.

The present invention also relates to at least a compound of formula (I)of the invention or of the composition of the invention for use for thetreatment of pathologies such as cholesterol, metabolic disorders,obesity, AIDS, and some congenital and genetic diseases such asNiemann-Pick disease type C1.

The present invention also relates to the use of at least one compoundof formula (I) of the invention or of the composition of the inventionfor the preparation of a medicine for the treatment of pathologies suchas cholesterol, metabolic disorders, obesity, AIDS, and some congenitaland genetic diseases such as Niemann-Pick disease type C1.

The present invention also relates to a method of treatment ofpathologies such as cholesterol, metabolic disorders, obesity, AIDS, andsome congenital and genetic diseases such as Niemann-Pick disease typeC1 comprising the administration of a therapeutically effective amountof at least one compound of formula (I) of the invention or of thecomposition of the invention to a patient in the need thereof.

The present invention will now be described with the help ofnon-limitative examples.

EXAMPLES

Commercially available chemicals were of reagent grade and used asreceived. All reactions requiring anhydrous conditions were carried outusing oven-dried glassware and under an atmosphere of dry Ar or N₂.Microwave reactions were carried out in a Biotage Initiator apparatus.The reactions under ultrasound were carried out with Elmasonic P30Happaratus with a frequency of 80 kHz and effective power of 100 W. Thereactions were monitored by thin layer chromatography (TLC) analysisusing silica gel precoated plates (Kieselgel 60F254, E. Merck).Compounds were visualized by UV irradiation and/or spraying withphosphomolybdic acid (PMA) stain, potassium permanganate solution orninhydrin stain, followed by charring at around 150° C. Flash columnchromatography was performed on Silica Gel 60 M (0.040-0.063 mm, E.Merck). The infrared spectra were measured with Perkin-ElmerSpectrometer. The ¹H and ¹³C NMR spectra were recorded on Bruker AvanceDPX 250 or Bruker Avance 400 Spectrometers. Chemical shifts are given inppm and are referenced to the deuterated solvent signal or to TMS asinternal standard and multiplicities are reported as s (singlet), d(doublet), t (triplet), q (quartet) and m (multiplet). Carbonmultiplicities were assigned by distortionless enhancement bypolarization transfer (DEPT) experiments. ¹H and ¹³C signals wereattributed on the basis of H—H and H—C correlations. High ResolutionMass spectra were performed on a Bruker Q-TOF MaXis spectrometer.

General Procedures:

Compounds of the invention have been synthesized following 10 generalprocedures, described as follow:

General Procedure 1:

A microwave vial was charged with bromomethylbenzene derivative (0.4mmol, 1 equiv), appropriated phenol derivative (0.44 mmol, 1.1 equiv),K₂CO₃ (0.8 mmol, 2 equiv), few crystals of NaI and dimethylformamide(DMF) (1.4 mL). The reaction mixture was heated under microwaveirradiation at 80° C. for 10 minutes. Then, resulted mixture was pouredinto water and extracted with ethyl acetate. Combined organic phaseswere washed with brine, dried over MgSO₄ and concentrated under vacuum.The residue was purified by column chromatography on silica gel(CH₂Cl₂/MeOH).

General Procedure 2:

To a solution of piperazine-Cbz derivative (1 equiv) in MeOH (1.6 mL)palladium on carbon (0.02 g, 0.19 mmol, 1.2 eq) was added and mixturewas stirred under hydrogen atmosphere overnight at room temperature.Then, palladium catalyst was filtered off. The filtrate was concentratedand dissolved in CH₂Cl₂ (3 mL). To the obtained solution were addedaldehyde derivative (1 equiv) and sodium triacetoxyborohydride (0.04 g,0.19 mmol, 1.2 equiv). The reaction mixture was stirred at roomtemperature till the completion (˜20 h), then after addition of water,the solution was extracted with ethyl acetate. The combined organicphases were washed with brine, dried over MgSO₄ and concentrated. Thecrude was purified by column chromatography (CH₂Cl₂/MeOH).

General Procedure 3:

A solution of aldehyde (1 equiv) in 40% NaHSO₃ (2 mL) was stirred for 1h at room temperature. Then a solution of 3,4-diaminobenzoic acid (0.30g, 1.97 mmol, 1 equiv) in ethanol (1 mL) was added. Reaction mixture wasstirred at 100° C. for 1-4 h, and then concentrated. Residue wasdissolved in water, and then the obtained mixture was acidified to pH3-4 by adding HCl. The resulting precipitate was collected by filtrationto give desired product.

General Procedure 4:

A solution of aldehyde (1 equiv) in 40% NaHSO₃ (4 mL) was stirred for 1h at room temperature, then a solution of methyl 3,4-diaminobenzoate(0.65 g, 3.94 mmol, 1 equiv) in ethanol (2 mL) was added. The resultingmixture was stirred at 100° C. for 1-4 h, and then concentrated. Theresidue was dissolved in water and extracted with ethyl acetate. Thecombined organic phases were dried over MgSO₄ and concentrated. Thecrude product was purified by flash column chromatography (PE/EtOAc orCH₂Cl₂/MeOH) to afford desired product.

General Procedure 5:

To a mixture of LiAlH₄ (0.03 g, 0.8 mmol, 2 equiv) in drytetrahydrofuran (THF) (1 mL), cooled at 0° C., a solution of methyl2-substituted-benzimidazole-5 carboxylate (1 equiv) in dry THE (1 mL)was slowly added. The ice bath was removed and the reaction mixture wasstirred for 2-4 h. After completion ethyl acetate and water were added.Then, the aqueous phase was extracted with ethyl acetate (3×) and thecombined organic phases were dried over MgSO₄ and concentrated to givethe desired product.

General Procedure 6:

To a flask with hydroxymethyl benzimidazole derivative (1 equiv) SOCl₂(0.84 mL, 11.6 mmol, 29 equiv) was added and the resulted mixture wasstirred for 2 h30 min at 80° C. After cooling to room temperature, SOCl₂was evaporated and the obtained solid was diluted with CH₂Cl₂ (4 mL) andcooled to 0° C. Then, to the obtained solution piperazine derivative (1equiv) and diisopropylethylamine (0.37 mL, 2.12 mmol, 5.3 equiv) wereadded. The ice bath was removed and the reaction mixture was stirred for16-19 h at room temperature. Then, the reaction mixture was washed withwater (4×), brine and dried over MgSO₄. After concentration, the crudeproduct was purified by column chromatography (CH₂Cl₂/MeOH) to give thedesired product.

General Procedure 7:

To a mixture of piperazine derivative (1.1 equiv) andbenzimidazole-carboxylic acid derivative (1 equiv) in DMF (1 mL),(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate(BOP) (0.24 g, 0.55 mmol, 1.3 equiv) and diisopropylethylamine (0.22 mL,1.26 mmol, 3 equiv) were added. The reaction mixture was stirred at roomtemperature for 16 h then NaCl_(sat) was added. The aqueous phase wasextracted with ethyl acetate (3×), then the combined organic phases werewashed with 5% NaHCO₃ and NaCl_(sat), dried over MgSO₄ and concentrated.The crude product was purified by column chromatography (PE/EtOAc orCH₂Cl₂/MeOH) to obtain the desired product.

General Procedure 8:

To a solution of Boc-piperazine derivative in CH₂Cl₂ TFA (0.6 mL) wasadded and the reaction mixture was stirred till completion, under N₂ atroom temperature. Then, the obtained mixture was concentrated and theresidue was dissolved in CH₂Cl₂ and NaHCO_(3sat) was added. The aqueousphase was extracted with CH₂Cl₂. The combined organic phases were washedwith water, dried over MgSO₄ and concentrated. The crude product wasused directly in the further step or purified by column chromatography(CH₂Cl₂/MeOH) to give the desired product.

General Procedure 9:

A microwave vial was charged with α,α-dibromo-m/p-xylene (0.40 g, 1.5mmol, 2 equiv), phosphite derivative (0.75 mmol, 1 equiv) and DMF (0.8mL). The reaction mixture was heated at 150° C. for 2 minutes throughmicrowave activation. Then, the mixture was poured into water and theproduct was extracted with ethyl acetate. The combined organic phaseswere washed with water and brine, then dried over MgSO₄ and concentratedunder vacuum. Purification by column chromatography on silica gel(PE/EtOAc or CH₂Cl₂/MeOH) gave the desired product.

General Procedure 10:

A microwave vial was charged with 2-substituted4,6-dichloro-1,3,5-triazine (0.9 mmol, 1 equiv), amine derivative (0.9mmol, 1 equiv), N,N-diisopropylethylamine (DIPEA) (0.17 mL, 0.99 mmol,1.1 equiv) and acetonitrile (3 mL). The reaction mixture was heated at150° C. under microwave irradiation, and then was concentrated. Theresulted crude product was dissolved in CH₂Cl₂ or ethyl acetate andwashed with 2M HCl and water. The collected organic phase was dried overMgSO₄ and concentrated to give the desired product.

General Procedure 11:

Trifluoroacetic acid (100 eq.) was added dropwise to a mixture ofBoc-compound (1 eq.) in CH₂Cl₂ (2:1 CH₂Cl₂/trifluoroacetic acid v/v).The reaction was stirred at room temperature for 2 h and then volatileswere removed under reduced pressure. The crude product was extractedwith ethyl acetate, washed with NaHCO₃ until pH 7, dried over MgSO₄,filtrated and concentrated under vacuum. Pure compounds were obtainedafter purification by flash column chromatography withdichloromethane/methanol (95:5) as eluent.

General Procedure 12:

To a flask containing benzimidazole derivative (1 eq.), SOCl₂ (29 eq.)was added and the resulted mixture was stirred for 2 h30 at 80° C. Aftercooling to room temperature, SOCl₂ was evaporated and the obtained solidwas diluted with acetonitrile (4 mL) and cooled to 0° C. Then, to theobtained solution, piperidine derivative (1 eq.) anddiisopropylethylamine (5.3 eq.) were added. The ice bath was removed andthe reaction mixture was allowed to stir for 16-19 h at roomtemperature. After concentration, the crude product was purified bycolumn chromatography (CH₂Cl₂/MeOH) to give the desired product.

Example 1: Synthesis ofN1-(benzyloxycarbonyl)-N4-[(2-phenyl-benzimidazol-5-yl)methyl]-piperazine(E1)

Procedure:

1. Synthesis of Compound (1) N-(benzyloxycarbonyl)-piperazine

To a cooled solution of imidazole at 0° C. (1.00 g, 14.7 mmol, 2 equiv)in CH₂Cl₂ (18 mL), benzyl chloroformate (1.03 mL, 7.35 mmol, 1 equiv)was slowly added. After 1 h45 of stirring the white solid (imidazolehydrochloride) was filtered off. The obtained filtrate was concentrated,and then solubilised in ethanol (17.5 mL). In another flask the solutionof piperazine dihydrochloride (1.75 g, 11.03 mmol, 1.5 equiv) in water(17.5 mL) was prepared, then added dropwisely to ethanolic solution ofCbz-imidazole. The resulted mixture was stirred for 4 h30 at roomtemperature and then concentrated to ¼^(th) of its volume. Obtainedaqueous phase was extracted with chloroform (4×) to remove thediacylated product, then NaOH_(sat) was added to the previous aqueousphase (pH 9-10). The resulted aqueous phase was extracted again withchloroform (4×) to recover the monoacylated product. The organic phasewith monoacylated product was washed with water (4×), dried over MgSO₄and concentrated to give (1) (0.809 g, 50% in two steps) as a colorlessoil.

2. Synthesis of Compound (2) 5-methyl carboxylate-2-phenyl-benzimidazole

The title compound was prepared from benzaldehyde (0.4 mL, 3.94 mmol, 1equiv) following the general procedure 4. Compound (2) (0.97 g, 97%) wasobtained as a white solid.

3. Synthesis of Compound (3) 5-hydroxymethyl-2-phenyl-benzimidazole

The title compound was prepared from (2) (0.10 g, 0.4 mmol, 1 equiv)following the general procedure 5. Compound (3) (0.09 g, quantitative)was obtained as a white solid.

4. Synthesis of Compound (E1)

The title compound was prepared from (3) (0.10 g, 0.4 mmol, 1 equiv) and(1) (0.09 g, 0.4 mmol, 1 equiv) following the general procedure 6.Compound (E1) (0.17 g, 87%) was obtained as a white solid.

Characterization:

¹H NMR: (400 MHz, CDCl₃) δ 11.08 (s, 1H, NH), 8.17-8.03 (m, 2H),7.67-7.46 (m, 2H), 7.45-7.39 (m, 3H), 7.37-7.29 (m, 5H), 7.20 (dd,J=8.3, 1.3 Hz, 1H), 5.15 (s, 2H, CH₂), 3.60 (s, 2H, CH₂), 3.51 (bs, 4H,CH₂), 2.42 (bs, 4H, CH₂).

¹³C NMR: (101 MHz, CDCl₃) δ 155.50, 152.36, 136.76, 130.23, 130.05,129.14, 128.63, 128.17, 127.96, 126.81, 124.37, 67.34 (CH₂), 63.35(CH₂), 52.76 (CH₂), 44.00 (CH₂).

HRMS (ESI): m/z [M+H]⁺ calcd for C₂₆H₂₇N₄O₂ 427.2129 found 427.2129.

IR (cm⁻¹): 3064, 2929, 2809, 1699, 1431, 1362, 1286, 1237, 1122, 1078,1001, 779, 762, 695.

Mp: 112° C.

R_(f): 0.53 (CH₂Cl₂/MeOH 9:1)

Example 2: Synthesis ofN1-[(2-benzhydryl-benzimidazol-5-yl)methyl]-N4-(benzyloxycarbonyl)-piperazine(E2)

Procedure:

1. Synthesis of Compound (4) 2-benzhydryl-5-methylcarboxylate-benzimidazole

The title compound was prepared from diphenylacetaldehyde (0.16 mL, 0.9mmol, 1 equiv) following the general procedure 4. Compound (4) (0.24 g,79%) was obtained as an amorphous creamy solid.

2. Synthesis of Compound (5) 2-benzhydryl-5-hydroxymethyl-benzimidazole

The title compound was prepared from (4) (0.21 g, 0.6 mmol, 1 equiv)following the general procedure 5. Compound (5) (0.19 g, quantitative)was obtained as an amorphous creamy solid.

3. Synthesis of Compound (E2)

The title compound was prepared from (5) (0.08 g, 0.25 mmol, 1 equiv)and (1) (0.055 g, 0.25 mmol, 1 equiv) following the general procedure 6.Compound (E2) (0.067 g, 51%) was obtained as an orange solid.

Characterization:

¹H NMR: (250 MHz, CDCl₃) δ 9.09 (s, 1H, NH), 7.86-7.30 (m, 13H),7.27-7.15 (m, 5H), 5.84 (s, 1H, CH), 5.14 (s, 2H, CH₂), 3.62 (s, 2H,CH₂), 3.56-3.39 (m, 4H, CH₂), 2.45 (d, J=4.2 Hz, 4H, CH₂).

¹³C NMR: (101 MHz, CDCl₃) δ 155.38, 140.66, 136.90, 129.03, 129.02,128.61, 128.12, 127.98, 127.49, 67.20 (CH₂), 63.35 (CH₂), 52.78 (CH₂),52.06 (CH), 43.99 (CH₂).

HRMS (ESI): m/z [M+H]⁺ calcd for C₃₃H₃₃N₄O₂ 517.2598 found 517.2599.

IR (cm⁻¹): 3029, 2930, 0811, 1696, 1429, 1239, 1122, 731, 697.

Mp: 100° C.

R_(f): 0.59 (CH₂Cl₂/MeOH 9:1)

Example 3: Synthesis ofN1-(benzyloxycarbonyl)-N4-[[2-(3-pyridyl)-benzimidazol-5-yl]methyl]-piperazine(E3)

Procedure:

1. Synthesis of Compound (6) 5-methylcarboxylate-2-(3-pyridyl)-benzimidazole

The title compound was prepared from 3-pyridine-carboxaldehyde (0.18 mL,1.98 mmol, 1.1 equiv) following the general procedure 4. Compound (6)(0.38 g, 82%) was obtained as a yellow solid.

2. Synthesis of Compound (7) 5-hydroxymethyl-2-(3-pyridyl)-benzimidazole

The title compound was prepared from (6) (0.12 g, 0.5 mmol, 1 equiv)following the general procedure 5. Compound (7) (0.11 g, quantitative)was obtained as a yellow solid.

3. Synthesis of Compound (E3)

The title compound was prepared from (7) (0.046 g, 0.22 mmol, 1 equiv)and (1) (0.048 g, 0.22 mmol, 1 equiv) following the general procedure 6.Compound (E3) (0.060 g, 69%) was obtained as a yellow solid.

Characterization:

¹H NMR: (400 MHz, CDCl₃) δ 12.68 (s, 1H, NH), 9.36 (s, 1H), 8.58 (d,J=3.8 Hz, 1H), 8.47 (d, J=8.0 Hz, 1H), 7.53 (s, 2H), 7.37-7.28 (m, 6H),7.19 (d, J=8.2 Hz, 1H), 5.14 (s, 2H, CH₂), 3.61 (s, 2H, CH₂), 3.52 (s,4H, CH₂), 2.44 (s, 4H, CH₂).

¹³C NMR: (101 MHz, CDCl₃) δ 155.43, 150.27, 149.45, 147.37, 136.67,134.69, 128.62, 128.18, 127.94, 126.83, 124.24, 67.37 (CH₂), 63.22(CH₂), 52.75 (CH₂), 43.82 (CH₂).

HRMS (ESI): m/z [M+H]⁺ calcd for C₂₅H₂₆N₅O₂ 428.2081 found 428.2079.

IR (cm⁻¹): 3035, 2928, 2810, 2164, 1696, 1429, 1121, 1001, 818, 733.

Mp: 90° C.

R_(f): 0.49 (CH₂Cl₂/MeOH 9:1)

Example 4: Synthesis ofN1-(benzyloxycarbonyl)-N4-[[2-(2-pyridyl)-benzimidazol-5-yl]methyl]-piperazine(E4)

Procedure:

1. Synthesis of Compound (8) 2-(2-pyridyl)-benzimidazole-5-carboxylicacid

To a mixture of 3,4-diaminobenzoic acid (0.6 g, 3.94 mmol, 1 equiv) inEtOH (6 mL) and solution of cooper acetate monohydrate (0.86 g, 4.33mmol, 1.1 equiv) in water (10 mL), 2-pyridine carboxaldehyde (0.42 mL,4.33 mmol, 1.1 equiv) was added. The resulting mixture was stirred for 2h at 100° C. Black precipitate was filtered off and dispersed in EtOH (4mL). Then, Na₂S.xH₂O (1.7 g) was added and the mixture was stirred for30 min at 100° C. The obtained solid was filtered off from hot solutionand washed with hot water on the filter. The filtrate was acidified withHCl (pH˜2) and then the resulted mixture was heating at 80° C. till theremoving of H₂S. The cooled mixture was filtered off, concentrated andrecrystallized from EtOH. The obtained dihydrochloride product was mixedwith an equivalent quantity of KOH in ethanol. The solid was filteredoff and the filtrate was concentrated to give (8) (0.447 g, 47%) as abrown solid.

2. Synthesis of Compound (9) 5-methylcarboxylate-2-(2-pyridyl)-benzimidazole

To the solution of (8) (0.15 g, 0.63 mmol, 1 equiv) in MeOH (1.1 mL),cooled at 0° C., SOCl₂ (0.07 mL, 0.98 mmol, 1.55 equiv) was slowlyadded. The reaction mixture was heated at 50° C. for 16 h. After coolingto room temperature the water was added and the mixture was concentratedto ¼^(th) of its volume. The residue was adjusted to pH 6 withNaHCO_(3sat), then extracted with EtOAc. The combined organic phaseswere dried over MgSO₄ and concentrated to give (9) (0.135 g, 85%) as abeige solid.

3. Synthesis of Compound (10)5-hydroxymethyl-2-(2-pyridyl)-benzimidazole

The title compound was prepared from (9) (0.08 g, 0.3 mmol, 1 equiv)following the general procedure 5. Compound (10) (0.07 g, quantitative)was obtained as a yellow solid.

4. Synthesis of Compound (E4)

The title compound was prepared from (10) (0.025 g, 0.11 mmol, 1 equiv)and (1) (0.024 g, 0.11 mmol, 1 equiv) following the general procedure 6.Compound (E4) (0.024 g, 51%) was obtained as a yellow solid.

Characterization:

¹H NMR: (400 MHz, CDCl₃) δ 10.87 (d, J=33.4 Hz, 1H, NH), 8.64 (d, J=4.7Hz, 1H), 8.44 (d, J=7.9 Hz, 1H), 7.87 (td, J=7.8, 1.4 Hz, 1H), 7.78 (s,1H), 7.58-7.29 (m, 7H), 7.27 (s, 1H), 5.14 (s, 2H, CH₂), 3.66 (s, 2H,CH₂), 3.58-3.43 (m, 4H, CH₂), 2.47 (s, 4H, CH₂).

¹³C NMR: (101 MHz, CDCl₃) δ 155.39, 149.26, 148.44, 137.42, 136.91,128.61, 128.11, 127.99, 124.69, 121.71, 67.21 (CH₂), 63.38 (CH₂), 52.86(CH₂), 43.97 (CH₂).

HRMS (ESI): m/z [M+H]⁺ calcd for C₂₅H₂₆N₅O₂ 428.2081 found 428.2082.

IR (cm⁻¹): 2930, 1693, 1596, 1445, 1285, 1236, 1121, 999, 965, 823, 795,738, 696.

Mp: 94° C.

R_(f): 0.53 (CH₂Cl₂/MeOH 9:1)

Example 5: Synthesis ofN1-(benzyloxycarbonyl)-N4-[[2-[4-(trifluoromethyl)phenyl]-benzimidazol-5-yl]methyl]-piperazine(E5)

Procedure:

1. Synthesis of Compound (11) 5-methylcarboxylate-2-[4-(trifluoromethyl)phenyl]-benzimidazole

The title compound was prepared from 4-trifluoromethyl-benzaldehyde(0.41 mL, 3.00 mmol, 1 equiv) following the general procedure 4.Compound (11) (0.90 g, 93%) was obtained as a white solid.

2. Synthesis of Compound (12)5-hydroxymethyl-2-[4-(trifluoromethyl)phenyl]-benzimidazole

The title compound was prepared from (11) (0.40 g, 1.25 mmol, 1 equiv)following the general procedure 5. Compound (12) (0.35 g, 94%) wasobtained as a white solid.

3. Synthesis of Compound (E5)

The title compound was prepared from (12) (0.20 g, 0.68 mmol, 1 equiv)and (1) (0.15 g, 0.68 mmol, 1 equiv) following the general procedure 6.Compound (E5) (0.29 g, 86%) was obtained as a white solid.

Characterization:

¹H NMR: (400 MHz, CDCl₃) δ 8.21 (d, J=8.1 Hz, 2H), 7.75 (s, 1H), 7.67(d, J=8.3 Hz, 2H), 7.50-7.31 (m, 6H), 7.28-7.18 (m, 1H), 5.19 (s, 2H,CH₂), 3.63 (s, 2H, CH₂), 3.54 (s, 4H, CH₂), 2.45 (s, 4H, CH₂).

¹³C NMR: (101 MHz, CDCl₃) δ 150.61, 133.42, 131.92, 128.67, 128.24,127.89, 126.97, 126.13, 126.09, 125.29, 122.59, 67.52 (CH₂), 63.33(CH₂), 52.74 (CH₂), 44.08 (CH₂).

¹⁹F NMR: (376 MHz, CDCl₃) δ −62.83.

HRMS (ESI): m/z [M+H]⁺ calcd for C₂₇H₂₆F₃N₄O₂ 495.2002 found 495.2001.

IR (cm⁻¹): 2938, 2810, 1674, 1620, 1434, 1322, 1238, 1166, 1117, 1065,1016, 1001, 964, 850, 822, 787, 750, 695, 666.

Mp: 90° C.

R_(f): 0.54 (CH₂Cl₂/MeOH 9:1)

Example 6: Synthesis ofN1-(benzyloxycarbonyl)-N4-[[2-[3-(trifluoromethyl)phenyl]-benzimidazol-5-yl]methyl]-piperazine(E6)

Procedure:

1. Synthesis of Compound (13) 5-methylcarboxylate-2-[3-(trifluoromethyl)phenyl]-benzimidazole

The title compound was prepared from 3-trifluoromethyl-benzaldehyde(0.24 mL, 1.8 mmol, 1 equiv) following the general procedure 4. Compound(13) (0.44 g, 76%) was obtained as a white solid.

2. Synthesis of Compound (14)5-hydroxymethyl-2-[3-(trifluoromethyl)phenyl]-benzimidazole

The title compound was prepared from (13) (0.31 g, 0.96 mmol, 1 equiv)following the general procedure 5. Compound (14) (0.27 g, 95%) wasobtained as a white solid.

3. Synthesis of Compound (E6)

The title compound was prepared from (14) (0.20 g, 0.68 mmol, 1 equiv)and (1) (0.15 g, 0.68 mmol, 1 equiv) following the general procedure 6.Compound (E6) (0.32 g, 95%) was obtained as a white solid.

Characterization:

¹H NMR: (400 MHz, CDCl₃) δ 8.36 (s, 1H), 8.30 (d, J=7.8 Hz, 1H),7.84-7.63 (m, 2H), 7.61-7.29 (m, 7H), 7.28-7.18 (m, 1H), 5.18 (s, 2H,CH₂), 3.65 (s, 2H, CH₂), 3.55 (s, 4H, CH₂), 2.46 (s, 4H, CH₂).

¹³C NMR: (101 MHz, CDCl₃) δ 150.65, 130.98, 129.87, 129.71, 128.65,128.21, 127.93, 126.65, 125.25, 123.56, 67.44 (CH₂), 63.34 (CH₂), 52.79(CH₂), 44.08 (CH₂).

¹⁹F NMR: (376 MHz, CDCl₃) δ −62.84.

HRMS (ESI): m/z [M+H]⁺ calcd for C₂₇H₂₆F₃N₄O₂ 495.2002 found 495.2002.

IR (cm⁻¹): 2902, 1698, 1670, 1434, 1417, 1327, 1280, 1237, 1168, 1120,1072, 1001, 800, 764, 728, 695, 651.

Mp: 88° C.

R_(f): 0.56 (CH₂Cl₂/MeOH 9:1)

Example 7: Synthesis ofN1-(benzyloxycarbonyl)-N4-(2-phenyl-benzimidazole-5-carbonyl)-piperazine(E7)

Procedure:

1. Synthesis of Compound (15) 2-phenyl-benzimidazole-5-carboxylic acid

The title compound was prepared from benzaldehyde (0.2 mL, 1.97 mmol, 1equiv) following the general procedure 3. Compound (15) (0.27 g, 62%)was obtained as a creamy solid.

2. Synthesis of Compound (E7)

The title compound was prepared from (15) (0.10 g, 0.4 mmol, 1 equiv)and (1) (0.10 g, 0.44 mmol, 1.1 equiv) following the general procedure7. Compound (E7) (0.14 g, 90%) was obtained as a white solid.

Characterization:

¹H NMR: (250 MHz, DMSO) δ 13.13 (s, 1H, NH), 8.19 (dd, J=8.0, 1.6 Hz,2H), 7.76-7.49 (m, 5H), 7.46-7.19 (m, 6H), 5.11 (s, 2H), 3.72-3.41 (m,8H).

¹³C NMR: (101 MHz, DMSO) δ 129.01, 128.42, 127.87, 127.61, 126.59, 66.37(O—CH₂), 43.79 (CH₂).

HRMS (ESI): m/z [M+H]⁺ calcd for C₂₆H₂₅N₄O₃: 441.1921, found 441.1917.

IR (cm⁻¹): 3065, 1687, 1611, 1427, 1228, 1011, 841, 695.

Mp: 146° C.

R_(f): 0.5 (EtOAc)

Example 8: Synthesis ofN1-(2-benzhydryl-benzimidazole-5-carbonyl)-N4-(benzyloxycarbonyl)-piperazine(E8)

Procedure:

1. Synthesis of Compound (16) 2-benzhydryl-benzimidazole-5-carboxylicacid

The title compound was prepared from diphenylacetaldehyde (0.18 mL, 1.00mmol, 1 equiv) following the general procedure 3. Compound (16) (0.17 g,52%) was obtained as a grey solid.

2. Synthesis of Compound (E8)

The title compound was prepared from (16) (0.06 g, 0.18 mmol, 1 equiv)and (1) (0.04 g, 0.20 mmol, 1.1 equiv) following the general procedure7. Compound (E8) (0.072 g, 75%) was obtained as an amorphous creamysolid.

Characterization:

¹H NMR: (400 MHz, CDCl₃) δ 10.54 (s, 1H, NH), 7.52 (bs, 1H), 7.44-7.32(m, 5H), 7.29-7.21 (m, 7H), 7.19-7.08 (m, 5H), 5.73 (s, 1H, CH), 5.15(s, 2H, O—CH₂), 3.50 (bs, 8H, CH₂).

¹³C NMR: (101 MHz, CDCl₃) δ 171.59, 155.32, 140.46, 136.48, 129.05,128.97, 128.76, 128.42, 128.20, 127.48, 67.70 (CH₂), 52.01 (CH), 44.07(CH₂).

HRMS (ESI): m/z [M+H]⁺ calcd for C₃₃H₃₁N₄O₃ 531.2391 found 531.2399.

IR (cm⁻¹): 3029, 1698, 1611, 1494, 1448, 1359, 1286, 1227, 1108, 1007,744, 697.

R_(f): 0.65 (CH₂Cl₂/MeOH 9:1)

Example 9: Synthesis ofN1-(benzyloxycarbonyl)-N4-[2-(3-pyridyl)-benzimidazole-5-carbonyl]-piperazine(E9)

Procedure:

1. Synthesis of Compound (17) 2-(3-pyridyl)-benzimidazole-5-carboxylicacid

The title compound was prepared from 3-pyridine-carboxaldehyde (0.19 mL,2.00 mmol, 1 equiv) following the general procedure 3. Compound (17)(0.46 g, 97%) was obtained as a beige solid.

2. Synthesis of Compound (E9)

The title compound was prepared from (17) (0.10 g, 0.42 mmol, 1 equiv)and (1) (0.10 g, 0.46 mmol, 1.1 equiv) following the general procedure7. Compound (E9) (0.18 g, 96%) was obtained as a yellow solid.

Characterization:

¹H NMR: (400 MHz, DMSO) δ 13.32 (s, 1H, NH), 9.35 (d, J=1.9 Hz, 1H),8.70 (dd, J=4.8, 1.5 Hz, 1H), 8.50 (dt, J=8.0, 1.8 Hz, 1H), 7.75 (s,1H), 7.60 (dd, J=8.0, 4.8 Hz, 2H), 7.44-7.34 (m, 4H), 7.34-7.27 (m, 2H),5.10 (s, 2H, O—CH₂), 3.78-3.39 (m, 8H, CH₂).

¹³C NMR: (101 MHz, DMSO) δ 154.45, 150.83, 147.63, 136.76, 133.94,128.43, 127.89, 127.60, 125.83, 124.08, 66.38 (CH₂), 44.63 (CH₂).

HRMS (ESI): m/z [M+H]⁺ calcd for C₂₅H₂₄N₅O₃ 442.1874 found 442.1875.

IR (cm⁻¹): 1686, 1614, 1429, 1362, 1287, 1235, 1116, 1013, 961, 838,741, 699.

Mp: 130° C.

R_(f): 0.46 (CH₂Cl₂/MeOH 9:1)

Example 10: Synthesis ofN1-(benzyloxycarbonyl)-N4-[2-(2-pyridyl)-benzimidazole-5-carbonyl]piperazine(E10)

Procedure:

The title compound was prepared from (8) (0.15 g, 0.63 mmol, 1 equiv)and (1) (0.15 g, 0.69 mmol, 1.1 equiv) following the general procedure7. Compound (E10) (0.22 g, 78%) was obtained as a yellow solid.

Characterization:

¹H NMR: (400 MHz, CDCl₃) δ 12.12-11.82 (m, 1H, NH), 8.59 (d, J=4.5 Hz,1H), 8.46 (dd, J=7.6, 4.2 Hz, 1H), 7.92-7.81 (m, 2H), 7.57-7.30 (m, 8H),5.16 (s, 2H, O—CH₂), 3.99-3.22 (m, 8H, CH₂).

¹³C NMR: (101 MHz, CDCl₃) δ 171.27, 171.10, 155.21, 152.69, 152.42,149.13, 148.11, 145.58, 143.84, 137.55, 136.39, 135.43, 134.19, 130.59,129.55, 128.59, 128.23, 128.02, 125.02, 123.51, 122.19, 122.10, 121.68,119.98, 119.13, 111.92, 111.37, 67.52 (CH₂), 43.96 (CH₂).

HRMS (ESI): m/z [M+H]⁺ calcd for C₂₅H₂₄N₅O₃ 442.1874 found 442.1873.

IR (cm⁻¹): 3062, 2321, 1697, 1615, 1421, 1226, 1106, 1010, 798, 743,696.

Mp: 165° C.

R_(f): 0.61 (CH₂Cl₂/MeOH 9:1)

Example 11: Synthesis ofN1-[[2-[(4-methoxycarbonylphenyl)methoxy]phenyl]methyl]-N4-[(2-phenyl-benzimidazol-5-yl)methyl]-piperazine(E11)

Procedure:

1. Synthesis of Compound (18) methyl 4-[(2-formylphenoxy)methyl]benzoate

The title compound was prepared from methyl 4-(bromomethyl) benzoate(0.25 g, 1.09 mmol, 1 equiv) and salicylaldehyde (0.13 mL, 1.20 mmol,1.1 equiv) following the general procedure 1. Compound (18) (0.30 g,quantitative) was obtained as a white solid.

2. Synthesis of Compound (E11)

The title compound was prepared from (E1) (0.07 g, 0.16 mmol, 1 equiv)and (18) (0.043 g, 0.16 mmol, 1 equiv) following the general procedure2. Compound (E11) (0.071 g, 79%) was obtained as an amorphous creamysolid.

Characterization:

¹H NMR: (400 MHz, CDCl₃) δ 11.33 (s, 1H, NH), 8.15-8.06 (m, 2H), 8.03(d, J=8.2 Hz, 2H), 7.66-7.32 (m, 8H), 7.21 (t, J=7.1 Hz, 1H), 7.15 (d,J=8.1 Hz, 1H), 6.94 (t, J=7.3 Hz, 1H), 6.86 (d, J=8.2 Hz, 1H), 5.08 (s,2H, CH₂), 3.93 (s, 3H, CH₃), 3.71-3.53 (m, 4H, CH₂), 2.80-2.33 (m, 8H,CH₂).

¹³C NMR: (101 MHz, CDCl₃) δ 167.23, 156.97, 152.38, 142.65, 131.57,130.23, 130.15, 130.02, 129.69, 129.11, 128.68, 127.09, 126.92, 124.55,121.13, 112.15, 70.69 (CH₂), 69.65 (CH₂), 63.25 (CH₂), 56.42 (CH₂),52.91 (CH₂), 52.79 (CH₂), 52.41 (CH₃).

HRMS (ESI): m/z [M+H]⁺ calcd for C₃₄H₃₅N₄O₃ 547.2704 found 547.2700.

IR (cm⁻¹): 3061, 2927, 2811, 1719, 1453, 1435, 1278, 1107, 756, 697.

R_(f): 0.4 (CH₂Cl₂/MeOH 9:1)

Example 12: Synthesis ofN1-[(2-benzhydryl-benzimidazol-5-yl)methyl]-N4-[[2-[(4-methoxycarbonylphenyl)methoxy]phenyl]methyl]-piperazine(E12)

Procedure:

The title compound was prepared from (E2) (0.018 g, 0.03 mmol, 1 equiv)and (18) (0.008 g, 0.03 mmol, 1 equiv) following the general procedure2. Compound (E12) (0.013 g, 60%) was obtained as an amorphous creamysolid.

Characterization:

¹H NMR: (250 MHz, CDCl₃) δ 9.10 (d, J=20.7 Hz, 1H, NH), 8.07 (d, J=8.3Hz, 2H), 7.66 (s, 1H), 7.54 (d, J=8.2 Hz, 2H), 7.45-7.13 (m, 14H),7.03-6.83 (m, 2H), 5.83 (s, 1H, CH), 5.15 (s, 2H, CH₂), 3.94 (s, 3H,CH₃), 3.67 (s, 4H, CH₂), 2.56 (s, 8H, CH₂).

¹³C NMR: (101 MHz, CDCl₃) δ 140.72, 129.96, 129.67, 129.02, 127.46,127.02, 121.06, 112.10, 69.63 (CH₂), 63.35 (CH₂), 56.43 (CH₂), 53.11(CH₂), 52.30 (CH₃), 52.07 (CH).

HRMS (ESI): m/z [M+H]⁺ calcd for C₄₁H₄₁N₄O₃ 637.3173 found 637.3167.

IR (cm⁻¹): 3027, 2930, 2810, 1719, 1666, 1492, 1452, 1416, 1279, 1238,1107, 1009, 753, 730, 698.

R_(f): 0.26 (CH₂Cl₂/MeOH 9:1)

Example 13: Synthesis ofN1-[[2-[(4-methoxycarbonylphenyl)methoxy]phenyl]methyl]-N4-[[2-(3-pyridyl)-benzimidazol-5-yl]methyl]-piperazine(E13)

Procedure:

The title compound was prepared from (E3) (0.059 g, 0.14 mmol, 1 equiv)and (18) (0.038 g, 0.14 mmol, 1 equiv) following the general procedure2. Compound (E13) (0.029 g, 38%) was obtained as an amorphous creamysolid.

Characterization:

¹H NMR: (400 MHz, CDCl₃) δ 10.18 (s, 1H), 9.42 (s, 1H), 8.63 (s, 1H),8.54 (d, J=7.5 Hz, 1H), 8.03 (dd, J=8.0, 1.9 Hz, 2H), 7.65-7.53 (m, 2H),7.45 (dd, J=7.2, 0.8 Hz, 2H), 7.40 (s, 1H), 7.34 (d, J=7.2 Hz, 1H), 7.23(t, J=7.7 Hz, 1H), 7.17 (d, J=8.1 Hz, 1H), 6.94 (t, J=7.3 Hz, 1H), 6.87(d, J=8.2 Hz, 1H), 5.09 (s, 2H, O—CH₂), 3.92 (s, 3H, CH₃), 3.83-3.67 (m,4H, CH₂), 2.75 (bs, 8H, CH₂).

¹³C NMR: (101 MHz, CDCl₃) δ 167.06, 157.01, 142.24, 134.93 (CH), 131.97,130.04, 129.84 (CH), 129.44 (CH), 127.09 (CH), 124.96 (CH), 121.29 (CH),112.15 (CH), 69.69 (CH₂), 62.31 (CH₂), 55.40 (CH₂), 52.38 (CH₃), 51.61(CH₂), 51.29 (CH₂).

HRMS (ESI): m/z [M+H]⁺ calcd for C₃₃H₃₄N₅O₃ 548.2656 found 548.2653.

IR (cm⁻¹): 2922, 2850, 1718, 1451, 1280, 1107, 1020, 757, 709, 656.

R_(f): 0.34 (CH₂Cl₂/MeOH 9:1)

Example 14: Synthesis ofN1-[[2-[(4-methoxycarbonylphenyl)methoxy]phenyl]methyl]-N4-[[2-(2-pyridyl)-benzimidazol-5-yl]methyl]-piperazine(E14)

Procedure

The title compound was prepared from (E4) (0.03 g, 0.07 mmol, 1 equiv)and (18) (0.02 g, 0.07 mmol, 1 equiv) following the general procedure 2.Compound (E14) (0.030 g, 79%) was obtained as a creamy solid.

Characterization:

¹H NMR: (250 MHz, DMSO) δ 8.62 (d, J=4.5 Hz, 1H), 8.46 (d, J=7.9 Hz,1H), 8.07 (d, J=8.2 Hz, 2H), 7.87 (t, J=7.7 Hz, 1H), 7.74-7.44 (m, 4H),7.41-7.30 (m, 2H), 7.22 (d, J=8.2 Hz, 2H), 7.02-6.84 (m, 2H), 5.13 (s,2H, CH₂), 3.94 (s, 3H, CH₃), 3.78 (s, 2H, CH₂), 3.72 (s, 2H, CH₂), 2.68(s, 8H, CH₂).

¹³C NMR: (101 MHz, CDCl₃) δ 166.97, 156.94, 151.12, 149.14, 148.41,142.47, 137.46, 131.64, 129.99, 129.74, 128.78, 126.91, 124.66, 121.83,121.13, 112.11, 69.63 (CH₂), 63.00 (CH₂), 55.87 (CH₂), 52.41 (CH₂),52.27 (CH₃).

HRMS (ESI): m/z [M+H]⁺ calcd for C₃₃H₃₄N₅O₃ 548.2656 found 548.2653.

IR (cm⁻¹): 2942, 2808, 1718, 1595, 1447, 1278, 1241, 1107, 1009, 795,755, 697.

R_(f): 0.24 (CH₂Cl₂/MeOH 9:1)

Example 15: Synthesis ofN1-[[2-[4-(trifluoromethyl)phenyl]-benzimidazol-5-yl]methyl]-N4-[[2-[(4-methoxycarbonylphenyl)methoxy]phenyl]methyl]-piperazine

Procedure:

The title compound was prepared from (E5) (0.10 g, 0.2 mmol, 1 equiv)and (18) (0.054 g, 0.2 mmol, 1 equiv) following the general procedure 2.Compound (E15) (0.05 g, 40%) was obtained as a creamy solid.

Characterization:

¹H NMR: (400 MHz, CDCl₃) δ 8.16 (d, J=8.1 Hz, 2H), 8.02 (d, J=8.3 Hz,2H), 7.89-7.31 (m, 7H), 7.25-7.13 (m, 2H), 6.96 (t, J=7.2 Hz, 1H), 6.87(d, J=8.1 Hz, 1H), 5.06 (s, 2H, CH₂), 3.95 (s, 3H, CH₃), 3.65 (s, CH₂),3.58 (s, 2H, CH₂), 2.67-2.36 (m, 8H, CH₂).

¹³C NMR: (101 MHz, CDCl₃) δ 167.14, 156.83, 150.35, 142.45, 133.38,131.64, 131.32, 129.79, 129.46, 128.52, 126.99, 126.86, 125.87, 125.83,125.17, 122.47, 120.93, 111.95, 69.47 (CH₂), 63.04 (CH₂), 56.54 (CH₂),53.07 (CH₂), 52.67 (CH₂), 52.24 (CH₃).

¹⁹F NMR: (376 MHz, CDCl₃) δ −62.80.

HRMS (ESI): m/z [M+H]⁺ calcd for C₃₅H₃₄F₃N₄O₃ 615.2578 found 615.2581.

IR (cm⁻¹): 2939, 2811, 1720, 1619, 1602, 1492, 1453, 1436, 1323, 1279,1240, 1165, 1108, 1065, 1016, 965, 849, 754, 695.

R_(f): 0.62 (CH₂Cl₂/MeOH 9:1)

Example 16: Synthesis ofN1-[[2-[3-(trifluoromethyl)phenyl]-benzimidazol-5-yl]methyl]-N4-[[2-[(4-methoxycarbonylphenyl)methoxy]phenyl]methyl]-piperazine(E16)

Procedure:

The title compound was prepared from (E6) (0.060 g, 0.12 mmol, 1 equiv)and (18) (0.032 g, 0.12 mmol, 1 equiv) following the general procedure2. Compound (E16) (0.023 g, 31%) was obtained as a white solid.

Characterization:

¹H NMR: (400 MHz, CDCl₃) δ 8.38 (s, 1H), 8.30 (d, J=7.7 Hz, 1H), 8.05(d, J=8.3 Hz, 2H), 7.78-7.39 (m, 6H), 7.36 (d, J=7.4 Hz, 1H), 7.26-7.15(m, 2H), 6.96 (t, J=7.4 Hz, 1H), 6.88 (d, J=8.1 Hz, 1H), 5.08 (s, 2H,CH₂), 3.96 (s, 3H, CH₃), 3.68 (s, 2H, CH₂), 3.62 (s, 2H, CH₂), 2.79-2.37(m, 8H, CH₂).

¹³C NMR: (101 MHz, CDCl₃) δ 156.99, 150.64, 142.55, 131.71, 131.38,131.11, 129.96, 129.64, 129.61, 128.76, 127.25, 126.53, 123.58, 121.13,112.07, 77.36, 69.66 (CH₂), 63.11 (CH₂), 56.39 (CH₂), 52.91 (CH₂), 52.69(CH₂), 52.41 (CH₃).

¹⁹F NMR: (376 MHz, CDCl₃) δ −62.75.

HRMS (ESI): m/z [M+H]⁺ calcd for C₃₅H₃₄F₃N₄O₃ 615.2578 found 615.2575.

IR (cm⁻¹): 2938, 2809, 2360, 2343, 2324, 1718, 1457, 1327, 1279, 1241,1167, 1120, 1108, 1072, 806, 756, 697.

Mp: 102° C.

R_(f): 0.47 (CH₂Cl₂/MeOH 9:1)

Example 17: Synthesis ofN1-[[2-[(4-methoxycarbonylphenyl)methoxy]phenyl]methyl]-N4-(2-phenyl-benzimidazole-5-carbonyl)-piperazine(E17)

Procedure:

The title compound was prepared from (E7) (0.046 g, 0.1 mmol, 1 equiv)and (18) (0.043 g, 0.1 mmol, 1 equiv) following the general procedure 2.Compound (E17) (0.034 g, 59%) was obtained as a white solid.

Characterization:

¹H NMR: (400 MHz, MeOD) δ 8.15-8.05 (m, 2H), 8.03 (d, J=8.4 Hz, 2H),7.67 (s, 2H), 7.61-7.52 (m, 5H), 7.38-7.27 (m, 2H), 7.27-7.18 (m, 1H),7.02 (d, J=7.8 Hz, 1H), 6.95 (dd, J=8.3, 7.4 Hz, 1H), 5.18 (s, 2H,—OCH₂), 3.89 (s, 3H CH₃), 3.74-3.51 (m, 6H, CH₂), 2.54 (bs, 4H, CH₂).

¹³C NMR: (101 MHz, MeOD) δ 158.36, 144.40, 132.49, 131.83, 130.76,130.72, 130.58, 130.25, 129.94, 128.28, 127.98, 126.65, 121.90, 113.38,70.48 (CH₂), 57.26 (CH₂), 52.63 (CH₃).

HRMS (ESI): m/z [M+H]⁺ calcd for C₃₄H₃₃N₄O₄ 561.2496 found 561.2496.

IR (cm⁻¹): 3224, 2926, 2796, 1720, 1618, 1442, 1233, 1104, 1018, 752,695.

Mp: 255° C.

R_(f): 0.5 (CH₂Cl₂/MeOH 9:1)

Example 18: Synthesis ofN1-(2-benzhydryl-benzimidazole-5-carbonyl)-N4-[[2-[(4-methoxycarbonylphenyl)methoxy]phenyl]methyl]-piperazine(E18)

Procedure:

The title compound was prepared from (E8) (0.029 g, 0.05 mmol, 1 equiv)and (18) (0.014 g, 0.05 mmol, 1 equiv) following the general procedure2. Compound (E18) (0.022 g, 63%) was obtained as a white solid.

Characterization:

¹H NMR: (250 MHz, CDCl₃) δ 9.98 (d, J=96.5 Hz, 1H, NH), 8.04 (d, J=8.0Hz, 2H), 7.76-7.57 (m, 1H), 7.51 (d, J=8.1 Hz, 2H), 7.43 (bs, 1H), 7.34(d, J=6.2 Hz, 2H), 7.28-7.10 (m, 11H), 7.05-6.83 (m, 2H), 5.77 (s, 1H,CH), 5.13 (s, 2H, O—CH₂), 3.90 (s, 3H, CH₃), 3.79-3.33 (m, 6H, CH₂),2.50 (bs, 4H, CH₂).

¹³C NMR: (101 MHz, CDCl₃) δ 171.14, 156.95, 140.53, 130.05, 129.83,129.08, 127.53, 121.19, 112.22, 69.70 (CH₂), 56.54 (CH₂), 52.40 (CH₃),52.09 (CH).

HRMS (ESI): m/z [M+H]⁺ calcd for C₄₁H₃₉N₄O₄ 651.2966 found 651.2961.

IR (cm⁻¹): 2922, 1719, 1603, 1433, 1279, 1235, 1106, 1016, 1001, 818,753, 698.

Mp: 196° C.

R_(f): 0.77 (CH₂Cl₂/MeOH 9:1)

Example 19: Synthesis ofN1-[[2-[(4-methoxycarbonylphenyl)methoxy]phenyl]methyl]-N4-[2-(3-pyridyl)-benzimidazole-5-carbonyl]-piperazine(E19)

Procedure:

The title compound was prepared from (E9) (0.07 g, 0.16 mmol, 1 equiv)and (18) (0.043 g, 0.16 mmol, 1 equiv) following the general procedure2. Compound (E19) (0.05 g, 55%) was obtained as a creamy solid.

Characterization:

¹H NMR: (400 MHz, CDCl₃) δ 9.35 (s, 1H), 8.61 (d, J=4.6 Hz, 1H), 8.42(d, J=7.8 Hz, 1H), 8.06 (d, J=7.0 Hz, 2H), 7.50 (t, J=12.8 Hz, 4H), 7.34(t, J=6.6 Hz, 2H), 7.27-7.21 (m, 1H), 7.19 (d, J=8.2 Hz, 1H), 6.98 (t,J=7.2 Hz, 1H), 6.91 (d, J=8.1 Hz, 1H), 5.15 (s, 2H, —OCH₂), 3.92 (s, 3H,CH₃), 3.86-3.38 (m, 6H, CH₂), 2.78-2.37 (m, 4H, CH₂).

¹³C NMR: (101 MHz, CDCl₃) δ 171.55, 167.13, 156.95, 150.72, 148.00,142.58, 134.81, 131.32, 130.07, 129.84, 128.90, 127.07, 126.38, 124.02,121.23, 112.23, 69.69 (CH₂), 56.40 (CH₂), 53.63 (CH₂), 52.43 (CH₃).

HRMS (ESI): m/z [M+H]⁺ calcd for C₃₃H₃₂N₅O₄ 562.2449 found 562.2445.

IR (cm⁻¹): 2949, 2321, 1981, 1717, 1602, 1435, 1281, 1237, 1108, 1020,840, 755, 704.

R_(f): 0.37 (CH₂Cl₂/MeOH 9:1)

Example 20: Synthesis ofN1-[[2-[(4-methoxycarbonylphenyl)methoxy]phenyl]methyl]-N4-[2-(2-pyridyl)-benzimidazole-5-carbonyl]-piperazine(E20)

Procedure:

The title compound was prepared from (E10) (0.08 g, 0.18 mmol, 1 equiv)and (18) (0.049 g, 0.18 mmol, 1 equiv) following the general procedure2. Compound (E20) (0.05 g, 50%) was obtained as a white solid.

Characterization:

¹H NMR: (400 MHz, CDCl₃) δ 11.27 (d, J=18.2 Hz, 1H, NH), 8.63 (d, J=4.5Hz, 1H), 8.45 (d, J=7.9 Hz, 1H), 8.07 (d, J=8.3 Hz, 2H), 7.95-7.77 (m,2H), 7.64-7.47 (m, 3H), 7.45-7.31 (m, 3H), 7.23 (dt, J=8.1, 1.7 Hz, 1H),6.97 (t, J=7.4 Hz, 1H), 6.90 (d, J=8.0 Hz, 1H), 5.14 (s, 2H, CH₂), 3.93(s, 3H, CH₃), 3.84-3.22 (m, 6H, CH₂), 2.56 (s, 4H, CH₂).

¹³C NMR: (101 MHz, CDCl₃) δ 167.04, 156.93, 149.35, 148.15, 142.63,137.62, 131.17, 130.05, 129.84, 128.65, 126.97, 126.28, 125.09, 122.08,121.15, 112.21, 69.66 (CH₂), 56.56 (CH₂), 53.24 (CH₂), 52.36 (CH₃).

HRMS (ESI): m/z [M+H]⁺ calcd for C₃₃H₃₂N₅O₄ 562.2449 found 562.2451.

IR (cm⁻¹): 2946, 1718, 1613, 1492, 1434, 1278, 1234, 1106, 1019, 997,798, 753, 696.

Mp: 96° C.

R_(f): 0.47 (CH₂Cl₂/MeOH 9:1)

Example 21: Synthesis ofN1-[4-(trifluoromethyl)benzyl]-N4-[(2-phenyl-benzimidazol-5-yl)methyl]-piperazine(E21)

Procedure:

The title compound was prepared from (3) (0.02 g, 0.09 mmol, 1 equiv)and 1-[4-(trifluoromethyl)-benzyl]piperazine (0.02 mL, 0.09 mmol, 1equiv) following the general procedure 6. Compound (E21) (0.04 g,quantitative) was obtained as a white solid.

Characterization:

¹H NMR: (400 MHz, CDCl₃) δ 11.75 (s, 1H, NH), 8.17-7.97 (m, 2H),7.62-7.45 (m, 4H), 7.42 (d, J=8.0 Hz, 2H), 7.39-7.33 (m, 3H), 7.20 (dd,J=8.3, 1.3 Hz, 1H), 3.59 (s, 2H), 3.51 (s, 2H), 2.69-2.22 (m, 8H).

¹³C NMR: (101 MHz, CDCl₃) δ 152.57, 142.70, 130.26 (CH), 130.14, 129.62,129.39 (CH), 129.30, 129.20 (CH), 126.96 (CH), 125.79, 125.32 (CH),125.29 (CH), 124.69 (CH), 123.09, 63.43 (CH₂), 62.57 (CH₂), 53.21 (CH₂),53.12 (CH₂).

HRMS (ESI): m/z [M+H]⁺ calcd for C₂₆H₂₆F₃N₄ 451.2104 found 451.2107.

IR (cm⁻¹): 2935, 2810, 1457, 1324, 1290, 1160, 1121, 1065, 1009, 808,701.

Mp: 178° C.

R_(f): 0.47 (CH₂Cl₂/MeOH 9:1)

Example 22: Synthesis ofN1-[(2-benzhydryl-benzimidazol-5-yl)methyl]-N4-[4-(trifluoromethyl)benzyl]-piperazine(E22)

Procedure:

The title compound was prepared from (5) (0.05 g, 0.16 mmol, 1 equiv)and 1-[4-(trifluoromethyl)-benzyl]piperazine (0.03 mL, 0.16 mmol, 1equiv) following the general procedure 6. Compound (E22) (0.06 g, 71%)was obtained as a white solid.

Characterization:

¹H NMR: (400 MHz, CDCl₃) δ 9.13 (d, J=31.8 Hz, 1H, NH), 7.71-7.61 (m,1H), 7.56 (d, J=8.2 Hz, 2H), 7.44 (d, J=8.0 Hz, 2H), 7.37-7.30 (m, 4H),7.27-7.16 (m, 8H), 5.79 (s, 1H, CH), 3.61 (d, J=8.0 Hz, 2H, CH₂), 3.55(s, 2H, CH₂), 2.48 (s, 8H, CH₂).

¹³C NMR: (101 MHz, CDCl₃) δ 140.68, 129.33, 129.02, 129.01, 127.48,125.27, 125.23, 119.27, 63.35 (CH₂), 62.56 (CH₂), 53.25 (CH₂), 53.13(CH₂), 52.04 (CH).

HRMS (ESI): m/z [M+H]⁺ calcd for C₃₃H₃₂F₃N₄ 541.2574 found 541.2575.

IR (cm⁻¹): 2945, 2817, 1065, 1120, 1161, 1289, 1161, 1120, 1065, 1016,730, 711, 700.

Mp: 236° C.

R_(f): 0.62 (CH₂Cl₂/MeOH 9:1)

Example 23: Synthesis ofN1-[4-(trifluoromethyl)benzyl]-N4-[[2-(3-pyridyl)-benzimidazol-5-yl]methyl]-piperazine(E23)

Procedure:

The title compound was prepared from (7) (0.035 g, 0.16 mmol, 1 equiv)and 1-[4-(trifluoromethyl)-benzyl]piperazine (0.03 mL, 0.16 mmol, 1equiv) following the general procedure 6. Compound (E23) (0.05 g, 70%)was obtained as a yellow solid.

Characterization:

¹H NMR: (400 MHz, CDCl₃) δ 12.47 (s, 1H, NH), 9.31 (s, 1H), 8.59 (d,J=3.6 Hz, 1H), 8.45 (d, J=8.0 Hz, 1H), 7.68-7.38 (m, 6H), 7.35 (dd,J=7.9, 4.8 Hz, 1H), 7.20 (d, J=8.2 Hz, 1H), 3.60 (s, 2H, CH₂), 3.52 (s,2H, CH₂), 2.62-2.26 (m, 8H, CH₂).

¹³C NMR: (101 MHz, CDCl₃) δ 150.29, 149.27, 147.21, 142.64, 134.88,129.39, 127.00, 125.36, 125.32, 124.41, 63.37 (CH₂), 62.56 (CH₂), 53.17(CH₂).

HRMS (ESI): m/z [M+H]⁺ calcd for C₂₅H₂₅F₃N₅ 425.2056 found 425.2052.

IR (cm⁻¹): 2932, 2811, 1417, 1322, 1160, 1118, 1065, 811, 706.

Mp: 138° C.

R_(f): 0.48 (CH₂Cl₂/MeOH 9:1)

Example 24: Synthesis ofN1-[4-(trifluoromethyl)benzyl]-N4-[[2-(2-pyridyl)-benzimidazol-5-yl]methyl]-piperazine(E24)

Procedure:

The title compound was prepared from (10) (0.02 g, 0.09 mmol, 1 equiv)and 1-[4-(trifluoromethyl)-benzyl]piperazine (0.02 mL, 0.09 mmol, 1equiv) following the general procedure 6. Compound (E24) (0.03 g, 80%)was obtained as an amorphous creamy solid.

Characterization:

¹H NMR: (400 MHz, CDCl₃) δ 10.80 (d, J=40.6 Hz, 1H, NH), 8.64 (d, J=3.9Hz, 1H), 8.44 (d, J=6.8 Hz, 1H), 7.87 (t, J=7.7 Hz, 1H), 7.81-7.70 (m,1H), 7.67-7.42 (m, 5H), 7.39-7.35 (m, 1H), 7.31-7.21 (m, 1H), 3.66 (d,J=9.6 Hz, 2H, CH₂), 3.56 (s, 2H, CH₂), 2.50 (s, 8H, CH₂).

¹³C NMR: (101 MHz, CDCl₃) δ 149.26, 149.26, 148.47, 143.92, 142.70,137.42, 134.06, 129.35, 125.67, 125.28, 124.64, 124.48, 121.67, 120.71,119.77, 111.69, 110.98, 63.40 (CH₂), 62.58 (CH₂), 53.32 (CH₂), 53.28(CH₂), 53.22 (CH₂), 53.07 (CH₂).

HRMS (ESI): m/z [M+H]⁺ calcd for C₂₅H₂₅F₃N₅ 452.2057 found 452.2058.

IR (cm⁻¹): 2935, 2811, 1447, 1324, 1160, 1119, 1065, 1009, 795.

R_(f): 0.54 (CH₂Cl₂/MeOH 9:1)

Example 25: Synthesis ofN1-[4-(trifluoromethyl)benzyl]-N4-(2-phenyl-benzimidazole-5-carbonyl)-piperazine(E25)

Procedure:

The title compound was prepared from (15) (0.05 g, 0.21 mmol, 1 equiv)and 1-[4-(trifluoromethyl)-benzyl]piperazine (0.05 mL, 0.23 mmol, 1.1equiv) following the general procedure 7. Compound (E25) (0.08 g, 86%)was obtained as a white solid.

Characterization:

¹H NMR: (250 MHz, CDCl₃) δ 12.82-12.11 (m, 1H, NH), 8.12 (dd, J=6.5, 3.0Hz, 2H), 7.77-7.43 (m, 5H), 7.41-7.26 (m, 4H), 7.20 (d, J=8.0 Hz, 1H),4.01-3.31 (m, 6H, CH₂), 2.45 (s, 4H, CH₂).

¹³C NMR: (101 MHz, CDCl₃) δ 171.65, 142.01, 130.39, 129.90, 129.74,129.57, 129.29, 128.97, 127.07, 125.46, 125.42, 122.96, 62.32 (CH₂),53.39 (CH₂), 52.75 (CH₂), 48.42 (CH₂), 42.84 (CH₂).

HRMS (ESI): m/z [M+H]⁺ calcd for C₂₆H₂₄F₃N₄O 465.1897 found 465.1895.

IR (cm⁻¹): 1616, 1576, 1443, 1420, 1321, 1313, 1224, 1164, 1155, 1103,1064, 1017, 1001, 824, 780, 774, 694, 640.

Mp: 220° C.

R_(f): 0.65 (CH₂Cl₂/MeOH 9:1)

Example 26: Synthesis ofN1-(2-benzhydryl-benzimidazole-5-carbonyl)-N4-[4-(trifluoromethyl)benzyl]-piperazine(E26)

Procedure:

The title compound was prepared from (16) (0.05 g, 0.15 mmol, 1 equiv)and 1-[4-(trifluoromethyl)-benzyl]piperazine (0.03 mL, 0.17 mmol, 1.1equiv) following the general procedure 7. Compound (E26) (0.07 g, 79%)was obtained as a yellow solid.

Characterization:

¹H NMR: (400 MHz, CDCl₃) δ 10.86 (s, 1H, NH), 7.50 (dd, J=55.5, 7.2 Hz,6H), 7.33-6.72 (m, 11H), 5.67 (s, 1H, CH), 4.01-3.14 (m, 6H, CH₂), 2.41(s, 4H, CH₂).

¹³C NMR: (101 MHz, CDCl₃) δ 171.35, 157.54, 142.11, 140.55, 129.92,129.59, 129.36 (CH), 129.06 (CH), 128.91 (CH), 127.38 (CH), 125.72,125.50 (CH), 125.46 (CH), 123.01, 62.43 (CH₂), 53.03 (CH₂), 51.96 (CH).

HRMS (ESI): m/z [M+H]⁺ calcd for C₃₃H₃₀N₄O 555.2366 found 555.2366.

IR (cm⁻¹): 2934, 2815, 1607, 1419, 1323, 1161, 1119, 1065, 1018, 1001,841, 824, 743, 699, 641.

Mp: 148° C.

R_(f): 0.45 (CH₂Cl₂/MeOH 9:1)

Example 27: Synthesis ofN1-[4-(trifluoromethyl)benzyl]-N4-[2-(3-pyridyl)-benzimidazole-5-carbonyl]-piperazine(E27)

Procedure:

The title compound was prepared from (17) (0.05 g, 0.21 mmol, 1 equiv)and 1-[4-(trifluoromethyl)-benzyl]piperazine (0.05 mL, 0.23 mmol, 1.1equiv) following the general procedure 7. Compound (E27) (0.096 g, 99%)was obtained as an amorphous creamy solid.

Characterization:

¹H NMR: (400 MHz, CDCl₃) δ 13.06 (s, 1H, NH), 9.33 (bs, 1H), 8.60 (d,J=4.7 Hz, 1H), 8.41 (d, J=8.0 Hz, 1H), 7.65-7.40 (m, 5H), 7.35-7.25 (m,2H), 7.18 (d, J=8.0 Hz, 1H), 3.82 (bs, 2H, CH₂), 3.62-3.42 (m, 4H, CH₂),2.59-2.28 (m, 4H, CH₂).

¹³C NMR: (101 MHz, CDCl₃) δ 171.57, 151.27, 150.64, 147.90, 141.93,141.13, 134.67, 130.20, 129.88, 129.56, 129.27, 129.16, 126.33, 125.62,125.44, 125.40, 123.95, 122.92, 62.25 (CH₂), 53.34 (CH₂), 52.68 (CH₂),50.57 (CH₂), 44.41 (CH₂).

HRMS (ESI): m/z [M+H]⁺ calcd for C₂₅H₂₃F₃N₅O 466.1849 found 466.1849.

IR (cm⁻¹): 3659, 2971, 2284, 2165, 2050, 1981, 1605, 1495, 1439, 1324,1118, 1065, 843, 707.

R_(f): 0.39 (CH₂Cl₂/MeOH 9:1)

Example 28: Synthesis ofN1-[4-(trifluoromethyl)benzyl]-N4-[2-(2-pyridyl)-benzimidazole-5-carbonyl]-piperazine(E28)

Procedure:

The title compound was prepared from (8) (0.05 g, 0.21 mmol, 1 equiv)and 1-[4-(trifluoromethyl)-benzyl]piperazine (0.05 mL, 0.23 mmol, 1.1equiv) following the general procedure 7. Compound (E28) (0.07 g, 76%)was obtained as a creamy solid.

Characterization:

¹H NMR: (250 MHz, CDCl₃) δ 11.75-11.15 (m, 1H, NH), 8.65 (d, J=4.8 Hz,1H), 8.47 (d, J=7.9 Hz, 1H), 8.05-7.73 (m, 2H), 7.62-7.47 (m, 5H),7.44-7.34 (m, 2H), 3.94-3.40 (m, 6H, CH₂), 2.49 (bs, 4H, CH₂).

¹³C NMR: (101 MHz, CDCl₃) δ 170.93, 149.28, 148.08, 142.06, 137.60,129.84, 129.52, 129.30, 125.65, 125.43, 125.39, 125.08, 123.74, 122.94,122.05, 119.98, 119.18, 111.76, 111.18, 62.42 (CH₂), 53.55 (CH₂).

HRMS (ESI): m/z [M+H]⁺ calcd for C₂₅H₂₃F₃N₅O 466.1849 found 466.1847.

IR (cm⁻¹): 1614, 1437, 1323, 1161, 1118, 1106, 1065, 1019, 997, 822,796, 727, 698, 642, 621.

R_(f): 0.27 (CH₂Cl₂/MeOH 9:1)

Example 29: Synthesis ofN1-[3-(trifluoromethoxy)benzyl]-N4-[(2-phenyl-benzimidazol-5-yl)methyl]-piperazine(E29)

Procedure:

The title compound was prepared from (3) (0.05 g, 0.22 mmol, 1 equiv)and 1-[3-(trifluoromethoxy)-benzyl]piperazine (0.05 mL, 0.22 mmol, 1equiv) following the general procedure 6. Compound (E29) (0.09 g, 88%)was obtained as a yellow solid.

Characterization:

¹H NMR: (400 MHz, CDCl₃) δ 8.24-8.06 (m, 2H), 7.59 (bs, 2H), 7.52-7.38(m, 3H), 7.31 (t, J=7.8 Hz, 1H), 7.21 (dd, J=12.9, 5.5 Hz, 3H), 7.10 (d,J=7.8 Hz, 1H), 3.69 (s, 2H, CH₂), 3.49 (s, 2H, CH₂), 2.79-2.26 (m, 8H,CH₂).

¹³C NMR: (101 MHz, CDCl₃) δ 152.44, 149.49, 140.73, 130.24, 130.03,129.64, 129.14, 127.38, 126.88, 124.72, 121.45, 119.62, 63.17 (CH₂),62.20 (CH₂), 52.91 (CH₂), 52.56 (CH₂).

HRMS (ESI): m/z [M+H]⁺ calcd for C₂₆H₂₆F₃N₄O 467.2053 found 467.2049.

IR (cm⁻¹): 2811, 1456, 1254, 1213, 1154, 1010, 778, 700, 633.

Mp: 80° C.

R_(f): 0.36 (CH₂Cl₂/MeOH 9:1)

Example 30: Synthesis ofN1-[(2-benzhydryl-benzimidazol-5-yl)methyl]-N4-[3-(trifluoromethoxy)benzyl]-piperazine(E30)

Procedure:

The title compound was prepared from (5) (0.05 g, 0.16 mmol, 1 equiv)and 1-[3-(trifluoromethoxy)-benzyl]piperazine (0.035 mL, 0.16 mmol, 1equiv) following the general procedure 6. Compound (E30) (0.06 g, 65%)was obtained as a white solid.

Characterization:

¹H NMR: (400 MHz, CDCl₃) δ 9.63-9.26 (m, 1H, NH), 7.66-7.57 (m, 1H),7.43-7.16 (m, 15H), 7.10 (d, J=8.0 Hz, 1H), 5.77 (s, 1H, CH), 3.61 (s,2H, CH₂), 3.51 (s, 2H, CH₂), 2.48 (s, 8H, CH₂).

¹³C NMR: (101 MHz, CDCl₃) δ 155.44, 149.45, 141.00, 140.69, 129.56,129.01, 128.97, 127.97, 127.43, 127.38, 127.31, 121.88, 121.48, 119.48,119.33, 63.33 (CH₂), 62.38 (CH₂), 53.10 (CH₂), 51.98 (CH₂).

HRMS (ESI): m/z [M+H]⁺ calcd for C₃₃H₃₂F₃N₄O 557.2523 found 557.2516.

IR (cm⁻¹): 2810, 1450, 1256, 1214, 1155, 1010, 868, 795, 699, 634.

Mp: 86° C.

R_(f): 0.49 (CH₂Cl₂/MeOH 9:1)

Example 31: Synthesis ofN1-[3-(trifluoromethoxy)benzyl]-N4-[[2-(3-pyridyl)-benzimidazol-5-yl]methyl]-piperazine(E31)

Procedure:

The title compound was prepared from (7) (0.04 g, 0.18 mmol, 1 equiv)and 1-[3-(trifluoromethoxy)-benzyl]piperazine (0.04 mL, 0.18 mmol, 1equiv) following the general procedure 6. Compound (E31) (0.055 g, 66%)was obtained as a yellow solid.

Characterization:

¹H NMR: (400 MHz, CDCl₃) δ 12.95 (s, 1H, NH), 9.33 (d, J=1.6 Hz, 1H),8.57 (dd, J=4.8, 1.4 Hz, 1H), 8.46 (d, J=8.0 Hz, 1H), 7.67-7.28 (m, 4H),7.26-7.15 (m, 3H), 7.09 (d, J=8.1 Hz, 1H), 3.59 (s, 2H, CH₂), 3.48 (s,2H, CH₂), 2.74-2.18 (m, 8H, CH₂).

¹³C NMR: (101 MHz, CDCl₃) δ 150.10, 149.46, 149.25, 147.15, 140.93,134.82, 129.58, 127.34, 126.99, 124.33, 121.87, 121.43, 119.52, 119.32,63.29 (CH₂), 62.32 (CH₂), 53.11 (CH₂), 53.00 (CH₂).

HRMS (ESI): m/z [M+H]⁺ calcd for C₂₅H₂₅F₃N₅O 468.2006 found 468.2001.

IR (cm⁻¹): 2810, 1445, 1255, 1213, 1155, 1010, 814, 795, 703, 632.

Mp; 110° C.

R_(f): 0.4 (CH₂Cl₂/MeOH 9:1)

Example 32: Synthesis ofN1-[3-(trifluoromethoxy)benzyl]-N4-[[2-(2-pyridyl)-benzimidazol-5-yl]methyl]-piperazine(E32)

Procedure:

The title compound was prepared from (10) (0.05 g, 0.22 mmol, 1 equiv)and 1-[3-(trifluoromethoxy)-benzyl]piperazine (0.05 mL, 0.22 mmol, 1equiv) following the general procedure 6. Compound (E32) (0.07 g, 68%)was obtained as a yellow solid.

Characterization:

¹H NMR: (250 MHz, CDCl₃) δ 10.75 (d, J=22.6 Hz, 1H, NH), 8.65 (d, J=4.6Hz, 1H), 8.45 (d, J=7.9 Hz, 1H), 7.88 (td, J=7.8, 1.5 Hz, 1H), 7.79 (s,1H), 7.53-7.40 (m, 1H), 7.38 (dd, J=5.3, 1.9 Hz, 1H), 7.32 (d, J=7.8 Hz,1H), 7.29-7.17 (m, 3H), 7.11 (d, J=7.8 Hz, 1H), 3.68 (s, 2H, CH₂), 3.55(s, 2H, CH₂), 2.53 (s, 8H, CH₂).

¹³C NMR: (101 MHz, CDCl₃) δ 149.48, 149.28, 148.46, 141.04, 137.39,129.57, 127.40, 124.65, 121.66, 121.50, 119.50, 63.42 (CH₂), 62.42(CH₂), 53.17 (CH₂).

HRMS (ESI): m/z [M+H]⁺ calcd for C₂₅H₂₅F₃N₅O 468.2006 found 468.2001.

IR (cm⁻¹): 1593, 1446, 1255, 1213, 1154, 1009, 794, 743, 700, 633, 621.

Mp: 65° C.

R_(f): 0.26 (CH₂Cl₂/MeOH 9:1)

Example 33: Synthesis ofN1-[3-(trifluoromethoxy)benzyl]-N4-(2-phenyl-benzimidazole-5-carbonyl)-piperazine(E33)

Procedure:

The title compound was prepared from (15) (0.05 g, 0.21 mmol, 1 equiv)and 1-[3-(trifluoromethoxy)-benzyl]piperazine (0.05 mL, 0.23 mmol, 1.1equiv) following the general procedure 7. Compound (E33) (0.054 g, 53%)was obtained as an amorphous creamy solid.

Characterization:

¹H NMR: (400 MHz, CDCl₃) δ 12.08 (s, 1H, NH), 8.10 (dd, J=6.6, 2.9 Hz,2H), 7.53 (bs, 2H), 7.43-7.37 (m, 3H), 7.34 (d, J=7.9 Hz, 1H), 7.27-7.17(m, 3H), 7.13 (d, J=7.4 Hz, 1H), 4.10-3.33 (m, 6H, CH₂), 2.66-2.22 (m,4H, CH₂).

¹³C NMR: (101 MHz, CDCl₃) δ 171.59, 153.96, 149.58, 140.42, 130.44,129.80, 129.71, 129.40, 129.01, 127.32, 127.04, 121.38, 119.84, 62.21(CH₂).

HRMS (ESI): m/z [M+H]⁺ calcd for C₂₆H₂₄F₃N₄O₂ 481.1846 found 481.1840.

IR (cm⁻¹): 1617, 1488, 1443, 1313, 1258, 1212, 1158, 1016, 1002, 956,895, 844, 780, 752, 693, 633.

R_(f): 0.44 (CH₂Cl₂/MeOH 9:1)

Example 34: Synthesis ofN1-(2-benzhydryl-benzimidazole-5-carbonyl)-N4-[3-(trifluoromethoxy)benzyl]-piperazine(E34)

Procedure:

The title compound was prepared from (16) (0.02 g, 0.06 mmol, 1 equiv)and 1-[3-(trifluoromethoxy)-benzyl]piperazine (0.015 mL, 0.07 mmol, 1.1equiv) following the general procedure 7. Compound (E34) (0.034 g, 98%)was obtained as a yellow solid.

Characterization:

¹H NMR: (250 MHz, CDCl₃) δ 10.20 (d, J=67.9 Hz, 1H, NH), 7.83-7.30 (m,6H), 7.26-6.91 (m, 11H), 5.78 (s, 1H, CH), 3.84-3.43 (m, 6H, CH₂),2.57-2.37 (m, 4H, CH₂).

¹³C NMR: (101 MHz, CDCl₃) δ 171.14, 160.89, 149.56, 140.46, 129.82,129.78, 129.01, 128.96, 127.44, 127.32, 127.24, 121.39, 119.81, 119.33,62.27 (CH₂), 53.47 (CH₂), 52.41 (CH₂), 52.00 (CH), 45.78 (CH₂), 40.10(CH₂).

HRMS (ESI): m/z [M+H]⁺ calcd for C₃₃H₃₀F₃N₄O₂ 571.2315 found 571.2312.

IR (cm⁻¹): 2922, 1611, 1489, 1443, 1302, 1255, 1213, 1150, 1002, 746,699, 633, 614.

Mp: 76° C.

R_(f): 0.65 (CH₂Cl₂/MeOH 9:1)

Example 35: Synthesis ofN1-[3-(trifluoromethoxy)benzyl]-N4-[2-(3-pyridyl)-benzimidazole-5-carbonyl]-piperazine(E35)

Procedure:

The title compound was prepared from (17) (0.05 g, 0.21 mmol, 1 equiv)and 1-[3-(trifluoromethoxy)-benzyl]piperazine (0.05 mL, 0.23 mmol, 1.1equiv) following the general procedure 7. Compound (E35) (0.095 g, 94%)was obtained as a white solid.

Characterization:

¹H NMR: (250 MHz, CDCl₃) δ 13.27 (s, 1H, NH), 9.37 (d, J=1.6 Hz, 1H),8.60 (dd, J=4.7, 1.1 Hz, 1H), 8.40 (d, J=8.0 Hz, 1H), 7.71 (bs, 1H),7.46-6.93 (m, 7H), 3.95-3.43 (m, 6H, CH₂), 2.50 (bs, 4H, CH₂).

¹³C NMR: (101 MHz, CDCl₃) δ 171.56, 150.64, 149.54, 149.52, 147.99,140.32, 134.63, 129.78, 127.27, 126.36, 123.88, 121.85, 121.32, 119.81,119.30, 62.12 (CH₂), 53.53 (CH₂), 53.26 (CH₂), 48.23 (CH₂), 42.68 (CH₂).

HRMS (ESI): m/z [M+H]⁺ calcd for C₂₅H₂₃F₃N₅O₂ 482.1798 found 482.1792.

IR (cm⁻¹): 1602, 1439, 1255, 1212, 1149, 1024, 1002, 810, 703, 633.

M 104° C.

R_(f): 0.49 (CH₂Cl₂/MeOH 9:1)

Example 36: Synthesis ofN1-[3-(trifluoromethoxy)benzyl]-N4-[2-(2-pyridyl)-benzimidazole-5-carbonyl]-piperazine(E36)

Procedure:

The title compound was prepared from (8) (0.05 g, 0.21 mmol, 1 equiv)and 1-[3-(trifluoromethoxy)-benzyl]piperazine (0.05 mL, 0.23 mmol, 1.1equiv) following the general procedure 7. Compound (E36) (0.08 g, 80%)was obtained as a white solid.

Characterization:

¹H NMR: (400 MHz, CDCl₃) δ 11.07 (d, J=21.8 Hz, 1H, NH), 8.66 (d, J=4.4Hz, 1H), 8.46 (d, J=6.9 Hz, 1H), 8.04-7.79 (m, 2H), 7.70-7.48 (m, 1H),7.47-7.32 (m, 3H), 7.25 (s, 2H), 7.13 (d, J=7.9 Hz, 1H), 4.26-3.17 (m,6H, CH₂), 2.50 (bs, 4H, CH₂).

¹³C NMR: (101 MHz, CDCl₃) δ 170.90, 170.77, 152.25, 149.57, 149.37,148.04, 140.48, 137.54, 129.77, 127.33, 125.09, 123.80, 121.98, 121.41,120.05, 119.80, 119.24, 111.69, 111.10, 100.13, 62.33 (CH₂), 53.24(CH₂).

HRMS (ESI): m/z [M+H]⁺ calcd for C₂₅H₂₃F₃N₅O₂ 482.1798 found 482.1792.

IR (cm⁻¹): 1619, 1449, 1263, 1212, 1259, 691.

Mp: 100° C.

R_(f): 0.43 (CH₂Cl₂/MeOH 9:1)

Example 37: Synthesis ofN1-[4-(trifluoromethoxy)benzyl]-N4-[(2-phenyl-benzimidazol-5-yl)methyl]-piperazine(E37)

Procedure:

The title compound was prepared from (3) (0.05 g, 0.22 mmol, 1 equiv)and 1-[4-(trifluoromethoxy)-benzyl]piperazine (0.05 mL, 0.22 mmol, 1equiv) following the general procedure 6. Compound (E37) (0.10 g, 98%)was obtained as an amorphous creamy solid.

Characterization:

¹H NMR: (400 MHz, CDCl₃) δ 8.23-8.11 (m, 2H), 7.54 (bs, 2H), 7.39-7.28(m, 5H), 7.18 (d, J=8.8 Hz, 1H), 7.13 (d, J=8.2 Hz, 2H), 3.60 (s, 2H,CH₂), 3.45 (s, 2H, CH₂), 2.60-2.29 (m, 8H, CH₂).

¹³C NMR: (101 MHz, CDCl₃) δ 152.63, 148.31, 136.98, 136.33, 131.88,130.40, 130.32, 130.17, 130.02, 129.01, 127.03, 124.47, 121.84, 120.95,120.79, 119.28, 63.25 (CH₂), 62.09 (CH₂), 52.89 (CH₂), 52.82 (CH₂).

HRMS (ESI): m/z [M+H]⁺ calcd for C₂₆H₂₆F₃N₄O 467.2053 found 467.2053.

IR (cm⁻¹): 2811, 1508, 1457, 1255, 1220, 1154, 1009, 810, 779, 698.

R_(f): 0.5 (CH₂Cl₂/MeOH 9:1)

Example 38: Synthesis ofN1-[(2-benzhydryl-benzimidazol-5-yl)methyl]-piperazine-N4-[4-(trifluoromethoxy)benzyl]-piperazine(E38)

Procedure:

The title compound was prepared from (5) (0.05 g, 0.16 mmol, 1 equiv)and 1-[4-(trifluoromethoxy)-benzyl]piperazine (0.034 mL, 0.16 mmol, 1equiv) following the general procedure 6. Compound (E38) (0.056 g, 64%)was obtained as an amorphous creamy solid.

Characterization:

¹H NMR: (400 MHz, CDCl₃) δ 9.42 (s, 1H, NH), 7.69-7.27 (m, 10H),7.24-7.10 (m, 7H), 5.80 (s, 1H, CH), 3.65 (s, 2H, CH₂), 3.51 (s, 2H,CH₂), 2.50 (s, 8H, CH₂).

¹³C NMR: (101 MHz, CDCl₃) δ 155.55, 148.40, 140.65, 136.89, 130.50,129.52, 129.01, 127.98, 127.46, 120.85, 119.33, 63.09 (CH₂), 62.10(CH₂), 52.79 (CH₂), 51.96 (CH₂) HRMS (ESI): m/z [M+H]⁺ calcd forC₃₃H₃₂F₃N₄O 557.2523 found 557.2514.

IR (cm⁻¹): 2811, 1507, 1495, 1454, 1256, 1220, 1155, 1009, 805, 734,698.

R_(f): 0.48 (CH₂Cl₂/MeOH 9:1)

Example 39: Synthesis ofN1-[4-(trifluoromethoxy)benzyl]-N4-[[2-(3-pyridyl)-benzimidazol-5-yl]methyl]-piperazine(E39)

Procedure:

The title compound was prepared from (7) (0.04 g, 0.18 mmol, 1 equiv)and 1-[4-(trifluoromethoxy)-benzyl]piperazine (0.04 mL, 0.18 mmol, 1equiv) following the general procedure 6. Compound (E39) (0.065 g, 78%)was obtained as a yellow solid.

Characterization:

¹H NMR: (400 MHz, CDCl₃) δ 12.50 (s, 1H, NH), 9.32 (d, J=1.7 Hz, 1H),8.60 (dd, J=4.8, 1.5 Hz, 1H), 8.50-8.39 (m, 1H), 7.70 (s, 1H), 7.52-7.29(m, 4H), 7.21 (dd, J=8.3, 1.2 Hz, 1H), 7.15 (d, J=7.9 Hz, 2H), 3.61 (s,2H, CH₂), 3.48 (s, 2H, CH₂), 2.70-2.22 (m, 8H, CH₂).

¹³C NMR: (101 MHz, CDCl₃) δ 150.27, 149.24, 148.37, 147.20, 137.09,134.75, 130.41, 126.92, 124.31, 121.89, 120.85, 63.30 (CH₂), 62.20(CH₂), 53.12 (CH₂).

HRMS (ESI): m/z [M+H]⁺ calcd for C₂₅H₂₅F₃N₅O 468.2006 found 468.2001.

IR (cm⁻¹): 2811, 1508, 1255, 1219, 1155, 1009, 810, 706.

Mp: 88° C.

R_(f): 0.43 (CH₂Cl₂/EtOH 8:2)

Example 40: Synthesis ofN1-[4-(trifluoromethoxy)benzyl]-N4-[[2-(2-pyridyl)-benzimidazol-5-yl]methyl]piperazine(E40)

Procedure:

The title compound was prepared from (10) (0.05 g, 0.22 mmol, 1 equiv)and 1-[4-(trifluoromethoxy)-benzyl]piperazine (0.046 mL, 0.22 mmol, 1equiv) following the general procedure 6. Compound (E40) (0.066 g, 63%)was obtained as a yellow solid.

Characterization:

¹H NMR: (400 MHz, CDCl₃) δ 11.02 (d, J=48.3 Hz, 1H, NH), 8.64 (d, J=4.4Hz, 1H), 8.46 (d, J=7.9 Hz, 1H), 7.88 (td, J=7.8, 1.3 Hz, 1H), 7.78 (bs,1H), 7.46-7.30 (m, 4H), 7.27 (s, 1H), 7.16 (d, J=8.0 Hz, 2H), 3.67 (s,2H, CH₂), 3.51 (s, 2H, CH₂), 2.51 (bs, 8H, CH₂).

¹³C NMR: (101 MHz, CDCl₃) δ 151.12, 149.21, 148.50, 148.35, 137.43,137.14, 130.45, 124.65, 121.75, 120.83, 119.33, 63.38 (CH₂), 62.25(CH₂), 53.15 (CH₂).

HRMS (ESI): m/z [M+H]⁺ calcd for C₂₅H₂₅F₃N₅O 468.2006 found 468.1999.

IR (cm⁻¹): 1507, 1447, 1255, 1220, 1156, 1009, 795, 743, 699, 620.

Mp: 64° C.

R_(f): 0.27 (CH₂Cl₂/MeOH 9:1)

Example 41: Synthesis ofN1-[4-(trifluoromethoxy)benzyl]-N4-(2-phenyl-benzimidazole-5-carbonyl)-piperazine(E41)

Procedure:

The title compound was prepared from (15) (0.05 g, 0.21 mmol, 1 equiv)and 1-[4-(trifluoromethoxy)-benzyl]piperazine (0.048 mL, 0.23 mmol, 1.1equiv) following the general procedure 7. Compound (E41) (0.084 g, 84%)was obtained as an amorphous creamy solid.

Characterization:

¹H NMR: (400 MHz, CDCl₃) δ 12.49 (s, 1H, NH), 8.17-7.97 (m, 2H),7.84-7.29 (m, 7H), 7.18 (d, J=7.9 Hz, 3H), 3.82 (bs, 2H, CH₂), 3.51 (s,4H, CH₂), 2.60-2.10 (m, 4H, CH₂).

¹³C NMR: (101 MHz, CDCl₃) δ 171.62, 148.55, 136.56, 130.39, 129.72,129.28, 128.98, 127.06, 121.01, 62.05.

HRMS (ESI): m/z [M+H]⁺ calcd for C₂₆H₂₄F₃N₄O₂ 481.1846 found 481.1840.

IR (cm⁻¹): 1602, 1436, 1277, 1253, 1220, 1158, 1004, 841, 778, 769, 691,674.

R_(f): 0.57 (CH₂Cl₂/MeOH 9:1)

Example 42: Synthesis ofN1-(2-benzhydryl-benzimidazole-5-carbonyl)-N4-[4-(trifluoromethoxy)benzyl]-piperazine(E42)

Procedure:

The title compound was prepared from (16) (0.02 g, 0.06 mmol, 1 equiv)and 1-[4-(trifluoromethoxy)-benzyl]piperazine (0.015 mL, 0.07 mmol, 1.1equiv) following the general procedure 7. Compound (E42) (0.028 g, 81%)was obtained as a white solid.

Characterization:

¹H NMR: (400 MHz, CDCl₃) δ 10.32 (bs, 1H, NH), 7.77-7.32 (m, 4H),7.31-7.23 (m, 6H), 7.21-7.03 (m, 7H), 5.74 (s, 1H, CH), 3.95-3.29 (m,6H, CH₂), 2.59-2.19 (m, 4H, CH₂).

¹³C NMR: (101 MHz, CDCl₃) δ 171.17, 148.53, 140.45, 136.57, 130.40,129.00, 128.94, 127.42, 121.00, 62.12 (CH₂), 51.97 (CH).

HRMS (ESI): m/z [M+H]⁺ calcd for C₃₃H₃₀F₃N₄O₂ 571.2315 found 571.2313.

IR (cm⁻¹): 1606, 1435, 1256, 1220, 1151, 1001, 699.

Mp: 120° C.

R_(f): 0.49 (CH₂Cl₂/MeOH 9:1)

Example 43: Synthesis ofN1-[4-(trifluoromethoxy)benzyl]-N4-[2-(3-pyridyl)-benzimidazole-5-carbonyl]-piperazine(E43)

Procedure:

The title compound was prepared from (17) (0.05 g, 0.21 mmol, 1 equiv)and 1-[4-(trifluoromethoxy)-benzyl]piperazine (0.048 mL, 0.23 mmol, 1.1equiv) following the general procedure 7. Compound (E43) (0.085 g, 85%)was obtained as an amorphous creamy solid.

Characterization:

¹H NMR: (400 MHz, CDCl₃) δ 13.10 (s, 1H, NH), 9.36 (d, J=1.6 Hz, 1H),8.62 (dd, J=4.8, 1.4 Hz, 1H), 8.48-8.35 (m, 1H), 7.86-7.27 (m, 5H), 7.19(d, J=7.9 Hz, 3H), 3.81 (bs, 2H, CH₂), 3.51 (s, 4H, CH₂), 2.47 (bs, 4H,CH₂)

¹³C NMR: (101 MHz, CDCl₃) δ 171.57, 151.32, 150.72, 148.58, 148.00,136.46, 134.68, 130.39, 129.56, 126.36, 123.91, 121.88, 121.02, 119.32,62.01 (CH₂).

HRMS (ESI): m/z [M+H]⁺ calcd for C₂₅H₂₃F₃N₅O₂ 482.1798 found 482.1794.

IR (cm⁻¹): 1604, 1438, 1255, 1220, 1157, 816, 706.

R_(f): 0.5 (CH₂Cl₂/MeOH 9:1)

Example 44: Synthesis ofN1-[4-(trifluoromethoxy)benzyl]-N4-[2-(2-pyridyl)-benzimidazole-5-carbonyl]piperazine(E44)

Procedure:

The title compound was prepared from (8) (0.05 g, 0.21 mmol, 1 equiv)and 1-[4-(trifluoromethoxy)-benzyl]piperazine (0.05 mL, 0.23 mmol, 1.1equiv) following the general procedure 7. Compound (E44) (0.079 g, 79%)was obtained as a white solid.

Characterization:

¹H NMR: (400 MHz, CDCl₃) δ 11.25 (bs, 1H, NH), 8.65 (d, J=4.2 Hz, 1H),8.46 (d, J=7.8 Hz, 1H), 8.02-7.77 (m, 2H), 7.65-7.45 (m, 1H), 7.45-7.29(m, 4H), 7.18 (d, J=7.8 Hz, 2H), 4.06-3.35 (m, 6H, CH₂), 2.49 (bs, 4H,CH₂).

¹³C NMR: (101 MHz, CDCl₃) δ 149.34, 148.53, 148.07, 137.56, 136.60,130.41, 125.08, 123.77, 121.95, 120.99, 119.21, 111.72, 62.16 (CH₂),53.29 (CH₂).

HRMS (ESI): m/z [M+H]⁺ calcd for C₂₅H₂₃F₃N₅O₂ 482.1798 found 482.1793.

IR (cm⁻¹): 1637, 1589, 1568, 1438, 1270, 1215, 1191, 1148, 1003, 835,818, 796, 745, 694.

Mp: 190° C.

R_(f): 0.5 (CH₂C2/MeOH 9:1)

Example 45: Synthesis ofN1-[(2-phenyl-benzimidazol-5-yl)methyl]-N4-(p-tolylcarbamoyl)-piperazine(E45)

Procedure:

1. Synthesis of Compound (19) N-tert-butoxycarbonyl-piperazine

To a solution of 1,4-piperazine (2.25 g, 26.1 mmol, 1.5 equiv) in CH₂Cl₂(50 mL) a solution of Boc₂O (3.80 g, 17.4 mmol, 1 equiv) in CH₂Cl₂ (25mL) was slowly added. The reaction mixture was stirred at roomtemperature for 21 h, then concentrated. To the residue, water was addedand the precipitated product was filtered off. The filtrate wasextracted with CH₂Cl₂ (3×) and the combined organic phases were driedover MgSO₄ and concentrated to give (19) (1.82 g, 56%) as a white solid.

2. Synthesis of Compound (20)N1-tert-butoxycarbonyl-N4-(p-tolylcarbamoyl)-piperazine

To a solution of (19) (0.4 g, 2.15 mmol, 1 equiv) in CH₂Cl₂ (12 mL)p-tolyl isocyanate (0.3 mL, 2.37 mmol, 1.1 equiv) was added. Thereaction mixture was stirred under N₂, at room temperature for 2 h andthen CH₂Cl₂ was added. The organic phase was washed with water andbrine, then dried over MgSO₄ and concentrated. The crude product waspurified by column chromatography (CH₂Cl₂/MeOH 96:4) to obtain thedesired product (20) (0.675 g, 98%) as a creamy solid.

3. Synthesis of Compound (21) N1-(p-tolylcarbamoyl)piperazine

The title compound was prepared from (20) (0.65 g, 2.0 mmol, 1 equiv)and TFA (2.5 mL, 32 mmol, 16 equiv) following the general procedure 8,stirring reaction mixture for 1 h30 min in CH₂Cl₂ (10 mL). Compound (21)(0.45 g, quantitative) was obtained as a brown solid.

4. Synthesis of Compound (E45)

The title compound was prepared from (3) (0.04 g, 0.18 mmol, 1 equiv)and (21) (0.04 g, 0.18 mmol, 1 equiv) following the general procedure 6.Compound (E45) (0.060 g, 79%) was obtained as a white solid.

Characterization:

¹H NMR: (400 MHz, MeOD) δ 8.11 (dd, J=8.0, 1.4 Hz, 2H), 7.66-7.47 (m,5H), 7.30 (d, J=8.3 Hz, 1H), 7.22 (d, J=8.4 Hz, 2H), 7.07 (d, J=8.3 Hz,2H), 3.70 (s, 2H, CH₂), 3.60-3.47 (m, 4H, CH₂), 2.66-2.43 (m, 4H, CH₂),2.28 (s, 3H, CH₃).

¹³C NMR: (101 MHz, MeOD) δ 158.12, 153.81, 138.12, 133.84, 131.40,130.99, 130.16, 130.04, 127.79, 122.50, 64.17 (CH₂), 53.92 (CH₂), 44.93(CH₂), 20.81 (CH₃).

HRMS (ESI): m/z [M+H]⁺ calcd for C₂₆H₂₈N₅O 426.2288 found 426.2286.

IR (cm⁻¹): 1625, 1607, 1470, 1437, 1406, 991, 808, 801, 772, 703, 687.

Mp: 211° C.

R_(f): 0.37 (CH₂Cl₂/MeOH 9:1)

Example 46: Synthesis ofN1-[(2-benzhydryl-benzimidazol-5-yl)methyl]-N4-(p-tolylcarbamoyl)-piperazine(E46)

Procedure:

The title compound was prepared from (5) (0.04 g, 0.13 mmol, 1 equiv)and (21) (0.03 g, 0.13 mmol, 1 equiv) following the general procedure 6.Compound (E46) (0.028 g, 43%) was obtained as an amorphous creamy solid.

Characterization:

¹H NMR: (250 MHz, CDCl₃) δ 7.53-7.33 (m, 2H), 7.23-7.03 (m, 13H),6.97-6.87 (m, 2H), 5.66 (s, 1H, CH), 3.53 (s, 2H, CH₂), 3.45-3.27 (m,4H, CH₂), 2.47-2.23 (m, 4H, CH₂), 2.14 (s, 3H, CH₃).

¹³C NMR: (63 MHz, MeOD) δ 158.09, 141.96, 138.10, 133.86, 130.45,130.05, 130.02, 129.72, 129.64, 128.88, 128.24, 125.42, 122.49, 64.11(CH₂), 53.81 (CH₂), 52.89 (CH), 44.79 (CH₂), 20.80 (CH₃).

HRMS (ESI): m/z [M+H]⁺ calcd for C₃₃H₄₄N₅O 516.2758 found 516.2755.

IR (cm⁻¹): 1633, 1515, 1448, 1413, 1243, 1001, 803, 744, 698, 644, 611.

R_(f) 0.53 (CH₂Cl₂/MeOH 9:1)

Example 47: Synthesis ofN1-[[2-(3-pyridyl)-benzimidazol-5-yl]methyl]-N4-(p-tolylcarbamoyl)-piperazine(E47)

Procedure:

The title compound was prepared from (7) (0.04 g, 0.18 mmol, 1 equiv)and (21) (0.04 g, 0.18 mmol, 1 equiv) following the general procedure 6.Compound (E47) (0.028 g, 36%) was obtained as a yellowish solid.

Characterization:

¹H NMR: (400 MHz, MeOD) δ 9.29 (d, J=1.6 Hz, 1H), 8.69 (dd, J=4.9, 1.4Hz, 1H), 8.57-8.49 (m, 1H), 7.73-7.58 (m, 3H), 7.37 (d, J=8.2 Hz, 1H),7.22 (d, J=8.4 Hz, 2H), 7.08 (d, J=8.2 Hz, 2H), 3.79 (s, 2H, CH₂),3.62-3.52 (m, 4H, CH₂), 2.68-2.53 (m, 4H, CH₂), 2.29 (s, 3H, CH₃).

¹³C NMR: (101 MHz, MeOD) δ 151.42, 148.38, 138.10, 136.00, 133.89,130.06, 125.68, 122.50, 63.96 (CH₂), 53.85 (CH₂), 44.80 (CH₂), 20.80(CH₃).

HRMS (ESI): m/z [M+H]⁺ calcd for C₂₅H₂₇N₆O 427.2241 found 427.2240.

IR (cm⁻¹): 2921, 1634, 1597, 1515, 1448, 1416, 1243, 1117, 1000, 810,747, 704, 611.

Mp: 174° C.

R_(f): 0.36 (CH₂Cl₂/MeOH 9:1)

Example 48: Synthesis ofN1-[[2-(2-pyridyl)-benzimidazol-5-yl]methyl]-N4-(p-tolylcarbamoyl)-piperazine(E48)

Procedure:

The title compound was prepared from (10) (0.04 g, 0.18 mmol, 1 equiv)and (21) (0.04 g, 0.18 mmol, 1 equiv) following the general procedure 6.Compound (E48) (0.033 g, 43%) was obtained as a beige solid.

Characterization:

¹H NMR: (400 MHz, MeOD) δ 8.74 (d, J=3.6 Hz, 1H), 8.30 (d, J=7.9 Hz,1H), 7.97 (t, J=7.6 Hz, 1H), 7.77-7.60 (m, 2H), 7.51-7.44 (m, 1H), 7.34(d, J=8.0 Hz, 1H), 7.22 (d, J=8.4 Hz, 2H), 7.08 (d, J=8.2 Hz, 2H), 3.72(s, 2H, CH₂), 3.60-3.50 (m, 4H, CH₂), 2.61-2.46 (m, 4H, CH₂), 2.28 (s,3H, CH₃).

¹³C NMR: (101 MHz, MeOD) δ 158.12, 138.13, 133.83, 130.04, 125.95,122.49, 64.14 (CH₂), 54.80 (CH₂), 53.93 (CH₂), 44.93 (CH₂), 20.80 (CH₃).

HRMS (ESI): m/z [M+H]⁺ calcd for C₂₅H₂₇N₆O 427.2241 found 427.2239.

IR (cm⁻¹): 1633, 1516, 1435, 1112, 1000, 189, 744, 697, 614.

Mp: 224° C.

R_(f): 0.40 (CH₂Cl₂/MeOH 9:1)

Example 49: Synthesis ofN1-[(2-phenyl-benzimidazol-5-yl)methyl]-N4-[[4-(trifluoromethyl)phenyl]carbamoyl]-piperazine(E49)

Procedure:

1. Synthesis of Compound (22)N1-tert-butoxycarbonyl-N4-[[4-(trifluoromethyl)phenyl]carbamoyl]-piperazine

The title compound was prepared from (19) (0.40 g, 2.15 mmol, 1 equiv)and 4-(trifluoro methyl)-phenyl isocyanate (0.34 mL, 2.37 mmol, 1.1 eq).Compound (22) (0.778 g, 97%) was obtained as a white solid.

2. Synthesis of Compound (23)N-[[4-(trifluoromethyl)phenyl]carbamoyl]-piperazine

The title compound was prepared from (22) (0.770 g, 1.9 mmol, 1 equiv)and TFA (2.3 mL, 30 mmol, 16 equiv) following the general procedure 8,stirring reaction mixture for 2 h in CH₂Cl₂ (9.5 mL). Compound (23)(0.439 g, 85%) was obtained as a white solid.

3. Synthesis of Compound (E49)

The title compound was prepared from (3) (0.04 g, 0.18 mmol, 1 equiv)and (23) (0.049 g, 0.18 mmol, 1 equiv) following the general procedure6. Compound (E49) (0.033 g, 38%) was obtained as a white solid.

Characterization:

¹H NMR: (400 MHz, MeOD) δ 8.15-8.07 (m, 2H), 7.65-7.49 (m, 9H), 7.29(dd, J=8.3, 1.0 Hz, 1H), 3.69 (s, 2H, CH₂), 3.61-3.52 (m, 4H, CH₂),2.62-2.49 (m, 4H, CH₂).

¹³C NMR: (101 MHz, MeOD) δ 157.17, 153.80, 144.86, 131.38, 130.97,130.14, 127.79, 127.25, 126.71, 126.68, 125.75, 125.34, 125.01, 124.56,120.93, 64.11 (CH₂), 53.87 (CH₂), 45.02 (CH₂).

HRMS (ESI): m/z [M+H]⁺ calcd for C₂₆H₂₅F₃N₅O 480.2006 found 480.2003.

IR (cm⁻¹): 1644, 1602, 1525, 1417, 1322, 1246, 1158, 1109, 1066, 1001,834, 692, 612.

Mp: 174° C.

R_(f): 0.45 (CH₂Cl₂/MeOH 9:1)

Example 50: Synthesis ofN1-[(2-benzhydryl-benzimidazol-5-yl)methyl]-N4-[[4-(trifluoromethyl)phenyl]carbamoyl]-piperazine(E50)

Procedure:

The title compound was prepared from (5) (0.04 g, 0.13 mmol, 1 equiv)and (23) (0.036 g, 0.13 mmol, 1 equiv) following the general procedure6. Compound (E50) (0.039 g, 53%) was obtained as a beige solid.

Characterization:

¹H NMR: (400 MHz, MeOD) δ 7.59-7.48 (m, 6H), 7.40-7.29 (m, 4H),7.29-7.21 (m, 7H), 5.81 (s, 1H, CH), 3.65 (s, 2H, CH₂), 3.58-3.48 (m,4H, CH₂), 2.55-2.42 (m, 4H, CH₂).

¹³C NMR: (101 MHz, MeOD) δ 157.73, 157.13, 144.85, 141.94, 132.58,130.46, 130.00, 129.94, 129.70, 129.61, 128.85, 128.21, 127.25, 126.72,126.69, 125.35, 125.03, 120.93, 64.08 (CH₂), 53.78 (CH₂), 52.88 (CH),44.95 (CH₂).

HRMS (ESI): m/z [M+H]⁺ calcd for C₃₃H₃₁F₃N₅O 570.2475 found 570.2472.

IR (cm⁻¹): 1645, 1445, 1416, 1322, 1245, 1161, 1110, 1067, 1001, 698.

Mp: 172° C.

R_(f): 0.41 (CH₂Cl₂/MeOH 9:1)

Example 51: Synthesis ofN1-[[2-(3-pyridyl)-benzimidazol-5-yl]methyl]-N4-[[4-(trifluoromethyl)phenyl]carbamoyl]-piperazine(E51)

Procedure:

The title compound was prepared from (7) (0.04 g, 0.18 mmol, 1 equiv)and (23) (0.049 g, 0.18 mmol, 1 equiv) following the general procedure6. Compound (E51) (0.041 g, 48%) was obtained as an amorphous creamysolid.

Characterization:

¹H NMR: (400 MHz, MeOD) δ 9.28 (s, 1H), 8.67 (d, J=3.8 Hz, 1H),8.54-8.37 (m, 1H), 7.62 (dd, J=7.5, 4.9 Hz, 3H), 7.55 (q, J=8.9 Hz, 4H),7.34 (d, J=8.1 Hz, 1H), 3.72 (s, 2H, CH₂), 3.65-3.48 (m, 4H, CH₂),2.64-2.21 (m, 4H, CH₂).

¹³C NMR: (101 MHz, MeOD) δ 157.17, 151.35, 150.61, 148.34, 144.84,135.94, 127.85, 127.25, 126.72, 126.69, 125.64, 125.36, 125.04, 124.56,120.93, 64.02 (CH₂), 53.88 (CH₂), 45.03 (CH₂).

HRMS (ESI): m/z [M+H]⁺ calcd for C₂₅H₂₄F₃N₆O 481.1958 found 481.1954.

IR (cm⁻¹): 1644, 1601, 1525, 1418, 1321, 1245, 1159, 1108, 1065, 1001,818, 705.

R_(f) 0.22 (CH₂Cl₂/MeOH 9:1)

Example 52: Synthesis ofN1-[[2-(2-pyridyl)-benzimidazol-5-yl]methyl]-N4-[[4-(trifluoromethyl)phenyl]carbamoyl]-piperazine(E52)

Procedure:

The title compound was prepared from (10) (0.04 g, 0.18 mmol, 1 equiv)and (23) (0.049 g, 0.18 mmol, 1 equiv) following the general procedure6. Compound (E52) (0.034 g, 40%) was obtained as an orange solid.

Characterization:

¹H NMR: (400 MHz, MeOD) δ 8.73 (d, J=3.3 Hz, 1H), 8.30 (d, J=7.9 Hz,1H), 7.97 (t, J=7.7 Hz, 1H), 7.76-7.61 (m, 2H), 7.56 (dd, J=14.6, 8.8Hz, 4H), 7.51-7.41 (m, 1H), 7.34 (d, J=8.1 Hz, 1H), 3.73 (s, 2H, CH₂),3.64-3.54 (m, 4H, CH₂), 2.63-2.47 (m, 4H, CH₂).

¹³C NMR: (101 MHz, MeOD) δ 157.20, 152.89, 150.90, 149.40, 144.87,138.52, 127.26, 126.74, 126.70, 125.95, 122.51, 120.95, 64.10 (CH₂),53.89 (CH₂), 45.03 (CH₂).

HRMS (ESI): m/z [M+H]⁺ calcd for C₂₅H₂₄F₃N₆O 481.1958 found 481.1954.

IR (cm⁻¹): 1646, 1445, 1244, 1160, 1109, 1066, 998, 793, 630, 620.

Mp: 136° C.

R_(f): 0.39 (CH₂Cl₂/MeOH 9:1)

Example 53: Synthesis ofN1-[2-(4-chlorophenoxy)acetyl]-N4-[(2-phenyl-benzimidazol-5-yl)methyl]-piperazine(E53)

Procedure:

1. Synthesis of Compound (24)N1-tert-butoxycarbonyl-N4-[2-(4-chlorophenoxy) acetyl]-piperazine

To a mixture of (19) (0.40 g, 2.15 mmol, 1 equiv) and Et₃N (0.45 mL,3.23 mmol, 1.5 equiv) in CH₂Cl₂ (11 mL), 4-chlorophenoxyacetyl chloride(0.37 mL, 2.37 mmol, 1.1 equiv) was added. The reaction mixture wasstirred overnight under N₂ atmosphere, then CH₂Cl₂ was added. Theorganic layer was washed with water and brine, then dried over MgSO₄ andconcentrated under vacuum. Purification by column chromatography onsilica gel (CH₂Cl₂/MeOH 97:3) gave (24) (0.74 g, 98%) as a brown solid.

2. Synthesis of Compound (25) N1-[2-(4-chlorophenoxy)acetyl]-piperazine

The title compound was prepared from (24) (0.72 g, 2.0 mmol) and TFA(0.6 mL) following the general procedure 8, stirring reaction mixtureovernight in CH₂Cl₂ (10 mL). Compound (25) (0.50 g, 97%) was obtained ascreamy oil.

3. Synthesis of Compound (E53)

The title compound was prepared from (3) (0.04 g, 0.18 mmol, 1 equiv)and (25) (0.046 g, 0.18 mmol, 1 equiv) following the general procedure6. Compound (E53) (0.069 g, 84%) was obtained as a white solid.

Characterization:

¹H NMR: (400 MHz, CDCl₃) δ 8.15 (dd, J=6.5, 3.1 Hz, 2H), 7.60-7.42 (m,2H), 7.42-7.32 (m, 3H), 7.25-7.11 (m, 3H), 6.87-6.75 (m, 2H), 4.67 (s,2H, —OCH₂), 3.67-3.43 (m, 6H, CH₂), 2.52-2.31 (m, 4H, CH₂).

¹³C NMR: (101 MHz, CDCl₃) δ 166.30, 156.49, 152.61, 132.14, 130.17,130.08, 129.57, 129.08, 126.89, 126.72, 124.17, 116.03, 67.64 (OCH₂),63.11 (CH₂), 53.09 (CH₂), 52.53 (CH₂), 45.40 (CH₂), 42.36 (CH₂).

HRMS (ESI): m/z [M+H]⁺ calcd for C₂₆H₂₆ClN₄O₂ 461.1739 found 461.1737.

IR (cm⁻¹): 1644, 1448, 1221, 1000, 821, 779, 728, 695, 641.

M 104° C.

R_(f): 0.55 (CH₂Cl₂/MeOH 9:1)

Example 54: Synthesis ofN1-[(2-benzhydryl-benzimidazol-5-yl)methyl]-N4-[2-(4-chlorophenoxy)acetyl]-piperazine(E54)

Procedure:

The title compound was prepared from (5) (0.04 g, 0.13 mmol, 1 equiv)and (25) (0.03 g, 0.13 mmol, 1 equiv) following the general procedure 6.Compound (E54) (0.027 g, 38%) was obtained as a beige solid.

Characterization:

¹H NMR: (400 MHz, CDCl₃) δ 7.64-7.33 (m, 7H), 7.28-7.16 (m, 8H),6.93-6.83 (m, 2H), 5.85 (s, 1H, CH), 4.66 (s, 2H, —OCH₂), 3.69-3.51 (m,6H, CH₂), 2.46 (s, 4H, CH₂).

¹³C NMR: (101 MHz, CDCl₃) δ 166.14, 156.59, 140.60, 129.63, 129.05,129.01, 127.53, 126.73, 116.10, 67.93 (CH₂), 63.11 (CH₂), 53.08 (CH₂),52.64 (CH₂), 52.04 (CH), 45.37 (CH₂), 42.22 (CH₂).

HRMS (ESI): m/z [M+H]⁺ calcd for C₃₃H₃₂ClN₄O₂ 551.2208 found 551.2200.

IR (cm⁻¹): 1673, 1650, 1490, 1454, 1421, 1284, 1245, 999, 820, 743, 695,640, 611.

Mp: 194° C.

R_(f): 0.41 (CH₂Cl₂/MeOH 9:1)

Example 55: Synthesis ofN1-[2-(4-chlorophenoxy)acetyl]-N4-[[2-(3-pyridyl)-benzimidazol-5-yl]methyl]-piperazine(E55)

Procedure:

The title compound was prepared from (7) (0.04 g, 0.18 mmol, 1 equiv)and (25) (0.046 g, 0.18 mmol, 1 equiv) following the general procedure6. Compound (E55) (0.034 g, 41%) was obtained as an amorphous creamysolid.

Characterization:

¹H NMR: (400 MHz, CDCl₃) δ 12.03 (s, 1H, NH), 9.35 (s, 1H), 8.65 (d,J=4.1 Hz, 1H), 8.49 (d, J=8.0 Hz, 1H), 7.56 (s, 2H), 7.41 (dd, J=7.9,4.8 Hz, 1H), 7.24-7.16 (m, 3H), 6.87-6.78 (m, 2H), 4.68 (s, 2H, CH₂),3.69-3.52 (m, 6H, CH₂), 2.63-1.91 (m, 4H, CH₂).

¹³C NMR: (101 MHz, CDCl₃) δ 166.35, 156.50, 150.52, 149.46, 147.47,134.63, 129.61, 126.78, 124.20, 116.04, 67.70 (CH₂), 63.08 (CH₂), 53.15(CH₂), 52.57 (CH₂), 45.40 (CH₂), 42.35 (CH₂).

HRMS (ESI): m/z [M+H]⁺ calcd for C₂₅H₂₅ClN₅O₂ 462.1691 found 462.1690.

IR (cm⁻¹): 1644, 1490, 1441, 1222, 1000, 821, 728, 707, 640.

R_(f) 0.34 (CH₂Cl₂/MeOH 9:1)

Example 56: Synthesis ofN1-[2-(4-chlorophenoxy)acetyl]-N4-[[2-(2-pyridyl)-benzimidazol-5-yl]methyl]-piperazine(E56)

Procedure:

The title compound was prepared from (10) (0.04 g, 0.18 mmol, 1 equiv)and (25) (0.046 g, 0.18 mmol, 1 equiv) following the general procedure6. Compound (E56) (0.038 g, 46%) was obtained as a beige solid.

Characterization:

¹H NMR: (400 MHz, CDCl₃) δ 10.73 (bs, 1H, NH), 8.66 (d, J=4.6 Hz, 1H),8.45 (d, J=7.9 Hz, 1H), 7.89 (td, J=7.9, 1.7 Hz, 1H), 7.82-7.76 (m, 1H),7.49-7.43 (m, 1H), 7.42-7.37 (m, 1H), 7.27-7.20 (m, 2H), 6.89 (dd,J=8.9, 1.3 Hz, 2H), 4.68 (d, J=2.0 Hz, 2H, —OCH₂), 3.71-3.54 (m, 6H,CH₂), 2.48 (s, 4H, CH₂).

¹³C NMR: (101 MHz, CDCl₃) δ 166.16, 156.63, 149.32, 148.38, 137.41,129.62, 124.75, 124.22, 121.67, 120.56, 119.98, 116.12, 111.14, 68.00(CH₂), 63.16 (CH₂), 53.08 (CH₂), 52.73 (CH₂), 45.53 (CH₂), 42.34 (CH₂).

HRMS (ESI): m/z [M+H]⁺ calcd for C₂₅H₂₅ClN₅O₂ 462.1691 found 462.1690.

IR (cm⁻¹): 1651, 1595, 1490, 1445, 1221, 1171, 1146, 1093, 1075, 1040,998, 823, 795, 695, 640, 612.

Mp: 138° C.

R_(f): 0.43 (CH₂Cl₂/MeOH 9:1)

Example 57: Synthesis ofN1-[2-[[4-(diethoxyphosphorylmethyl)phenyl]methoxy]phenyl]]-N4-[[2-[3-(trifluoromethyl)phenyl]-benzimidazol-5-yl]methyl]-piperazine

Procedure:

1. Synthesis of Compound (26) diethyl 4-(bromomethyl)benzylphosphonate

The title compound was prepared from α,α-dibromo-p-xylene (0.40 g, 1.5mmol, 2 equiv) and triethyl phosphite (0.13 mL, 0.75 mmol, 1 equiv)following the general procedure 9. Compound (26) (0.21 g, 88%) wasobtained as a colorless oil.

2. Synthesis of Compound (27)2-[[4-(diethoxyphosphorylmethyl)phenyl]methoxy]benzaldehyde

The title compound was prepared from (26) (0.13 g, 0.40 mmol, 1 equiv)and salicylaldehyde (0.05 mL, 0.44 mmol, 1.1 equiv) following thegeneral procedure 1. Compound (27) (0.14 g, 94%) was obtained as acolorless oil.

3. Synthesis of Compound (E57)

The title compound was prepared from (E6) (0.06 g, 0.12 mmol, 1 equiv)and (27) (0.043 g, 0.12 mmol, 1 equiv) following the general procedure2. Compound (E57) (0.027 g, 31%) was obtained as an amorphous whitesolid.

Characterization:

¹H NMR: (400 MHz, CDCl₃) δ 8.55 (s, 1H), 8.46 (d, J=7.4 Hz, 1H),7.70-7.36 (m, 6H), 7.33 (s, 3H), 7.25-6.88 (m, 4H), 4.98 (s, 2H, CH₂),4.13-3.93 (m, 4H, CH₂), 3.70 (s, 4H, CH₂), 3.23 (d, J=21.7 Hz, 2H, CH₂),2.62 (bs, 8H, CH₂), 1.26 (t, J=7.0 Hz, 6H, CH₃).

¹³C NMR: (101 MHz, CDCl₃) δ 157.22, 150.86, 135.79, 131.42, 131.05,130.96, 130.09, 129.94, 129.88, 129.26, 127.94, 123.64, 120.97, 111.90,69.95 (CH₂), 62.54 (CH₂), 62.47 (CH₂), 62.39 (CH₂), 55.61 (CH₂), 52.07(CH₂), 51.74 (CH₂), 34.10 (CH₂), 32.72 (CH₂), 16.39 (CH₃), 16.33 (CH₃).

¹⁹F NMR: (376 MHz, CDCl₃) δ −62.62. ³¹P NMR: (162 MHz, CDCl₃) δ 26.18.

HRMS (ESI): m/z [M+H]⁺ calcd for C₃₈H₄₃F₃N₄O₄P 707.2969 found 707.2962.

IR (cm⁻¹): 2931, 1814, 1455, 1328, 1225, 1165, 1124, 1165, 1124, 1071,1050, 1021, 964, 849, 810, 754, 720, 700.

R_(f): 0.41 (CH₂Cl₂/MeOH 9:1)

Example 58: Synthesis ofN1-[2-[[4-(diethoxyphosphorylmethyl)phenyl]methoxy]phenyl]]-N4-[[2-[4-(trifluoromethyl)phenyl]-benzimidazol-5-yl]methyl]-piperazine(E58)

Procedure:

The title compound was prepared from (E5) (0.10 g, 0.20 mmol, 1 equiv)and (27) (0.072 g, 0.20 mmol, 1 equiv) following the general procedure2. Compound (E58) (0.040 g, 28%) was obtained as an amorphous creamysolid.

Characterization:

¹H NMR: (400 MHz, CDCl₃) δ 8.32 (s, 2H), 7.81-7.54 (m, 3H), 7.51-7.07(m, 8H), 7.02-6.84 (m, 2H), 4.99 (s, 2H, CH₂), 4.18-3.90 (m, 4H, CH₂),3.61 (s, 4H, CH₂), 3.23 (d, J=21.5 Hz, 2H, CH₂), 2.49 (s, 8H, CH₂),1.35-1.17 (m, 6H, CH₃).

¹³C NMR: (101 MHz, CDCl₃) δ 157.07, 150.64, 136.13, 136.10, 133.84,131.31, 130.77, 130.68, 129.89, 129.82, 128.36, 127.75, 127.05, 125.70,125.66, 125.29, 122.59, 120.81, 111.92, 69.80 (CH₂), 62.89 (CH₂), 62.49(CH₂), 56.21 (CH₂), 52.97 (CH₂), 52.72 (CH₂), 33.40 (d, J=138.6 Hz,P—CH₂), 16.41 (CH₃), 16.36 (CH₃).

¹⁹F NMR: (376 MHz, CDCl₃) δ −62.73. ³¹P NMR: (162 MHz, CDCl₃) 26.31.

HRMS (ESI): m/z [M+H]⁺ calcd for C₃₈H₄₃F₃N₄O₄P 707.2969 found 707.2959.

IR (cm⁻¹): 2933, 2810, 1620, 1491, 1453, 1323, 1292, 1224, 1063, 1120,1065, 1051, 1017, 963, 851, 830, 788, 752, 731, 695.

R_(f): 0.41 (CH₂Cl₂/MeOH 9:1)

Example 59: Synthesis ofN1-[2-[[3-(diethoxyphosphorylmethyl)phenyl]methoxy]phenyl]]-N4-[[2-[3-(trifluoromethyl)phenyl]-benzimidazol-5-yl]methyl]-piperazine(E59)

Procedure.

1. Synthesis of Compound (28) diethyl 3-(bromomethyl)benzylphosphonate

The title compound was prepared from α,α-dibromo-m-xylene (0.40 g, 1.5mmol, 2 equiv) and triethyl phosphite (0.13 mL, 0.75 mmol, 1 equiv)following the general procedure 9.

Compound (28) (0.23 g, 94%) was obtained as a colorless oil.

2. Synthesis of Compound (29)2-[[3-(diethoxyphosphorylmethyl)phenyl]methoxy]benzaldehyde

The title compound was prepared from (28) (0.18 g, 0.56 mmol, 1 eq) andsalicylaldehyde (0.07 mL, 0.62 mmol, 1.1 equiv) following the generalprocedure 1. Compound (29) (0.19 g, 93%) was obtained as a colorlessoil.

3. Synthesis of Compound (E59)

The title compound was prepared from (E6) (0.06 g, 0.12 mmol, 1 equiv)and (29) (0.043 g, 0.12 mmol, 1 equiv) following the general procedure2. Compound (E59) (0.028 g, 33%) was obtained as an amorphous creamysolid.

Characterization:

¹H NMR: (400 MHz, CDCl₃) δ 8.53 (s, 1H), 8.44 (d, J=7.8 Hz, 1H),7.70-7.63 (m, 1H), 7.63-7.48 (m, 3H), 7.44-7.32 (m, 2H), 7.29-7.20 (m,4H), 7.13 (d, J=8.3 Hz, 1H), 7.03-6.84 (m, 2H), 5.01 (s, 2H, CH₂),4.11-3.96 (m, 4H, CH₂), 3.76 (s, 2H CH₂), 3.68 (s, 2H CH₂), 3.23 (d,J=21.5 Hz, 2H, CH₂), 2.66 (bs, 8H, CH₂), 1.24 (t, J=7.1 Hz, 6H, CH₃).

¹³C NMR: (101 MHz, CDCl₃) δ 157.05, 150.82, 137.44, 137.41, 132.00,131.82, 131.72, 131.28, 131.08, 130.04, 129.31, 129.23, 129.17, 129.02,128.79, 128.75, 128.70, 128.63, 126.13, 125.99, 125.34, 124.06, 123.59,122.63, 120.95, 111.95, 69.82 (CH₂), 62.56 (CH₂), 62.49 (CH₂), 62.37(CH₂), 55.26 (CH₂), 52.04 (CH₂), 51.96 (CH₂), 34.45 (CH₂), 33.08 (CH₂),16.37 (CH₃), 16.31 (CH₃).

¹⁹F NMR: (376 MHz, CDCl₃) δ −62.65. ³¹P NMR: (162 MHz, CDCl₃) δ 26.13.

HRMS (ESI): m/z [M+H]⁺ calcd for C₃₈H₄₃F₃N₄O₄P 707.2969 found 707.2960.

IR (cm⁻¹): 2930, 2810, 1601, 1492, 1455, 1404, 1328, 1287, 1229, 1165,1124, 1071, 1050, 1024, 965, 847, 807, 754, 697, 652.

R_(f): 0.32 (CH₂Cl₂/MeOH 9:1)

Example 60: Synthesis ofN1-[2-[[3-(diethoxyphosphorylmethyl)phenyl]methoxy]phenyl]]-N4-[[2-[4-(trifluoromethyl)phenyl]-benzimidazol-5-yl]methyl]-piperazine(E60)

Procedure:

The title compound was prepared from (E5) (0.10 g, 0.20 mmol, 1 equiv)and (29) (0.072 g, 0.20 mmol, 1 equiv) following the general procedure2. Compound (E60) (0.035 g, 25%) was obtained as an amorphous creamysolid.

Characterization:

¹H NMR: (400 MHz, CDCl₃) δ 8.31 (d, J=5.8 Hz, 2H), 7.79-7.35 (m, 6H),7.33-7.07 (m, 4H), 7.00-6.92 (m, 1H), 6.88 (d, J=8.0 Hz, 1H), 5.00 (s,2H, CH₂), 4.14-3.95 (m, 4H, CH₂), 3.66 (s, 2H, CH₂), 3.62 (s, 2H, CH₂),3.23 (d, J=21.4 Hz, 2H, P—CH₂), 2.55 (bs, 8H, CH₂), 1.25 (t, J=7.0 Hz,6H, CH₃).

¹³C NMR: (101 MHz, CDCl₃) δ 157.07, 150.66, 137.82, 137.79, 133.90,131.81, 131.71, 131.12, 129.24, 129.18, 128.89, 128.68, 128.56, 127.08,126.06, 125.83, 125.79, 125.43, 122.73, 120.96, 112.04, 69.86 (CH₂),62.71 (CH₂), 62.64 (CH₂), 56.08 (CH₂), 53.08 (CH₂), 52.94 (CH₂), 33.89(d, J=138.1 Hz, (P—CH₂), 16.54 (CH₃), 16.49 (CH₃).

¹⁹F NMR: (376 MHz, CDCl₃) δ −62.74.

³¹P NMR: (162 MHz, CDCl₃) δ 26.21.

HRMS (ESI): m/z [M+H]⁺ calcd for C₃₈H₄₃F₃N₄O₄P 707.2969 found 707.2961.

IR (cm⁻¹): 2934, 2810, 1620, 1600, 1492, 1453, 1323, 1228, 1163, 1120,1065, 1051, 1016, 964, 908, 850, 813, 788, 752, 729, 695.

R_(f): 0.37 (CH₂Cl₂/MeOH 9:1)

Example 61: Synthesis of (E61)6-[[4-[2-[[3-(diethoxyphosphorylmethyl)phenyl]-methoxy]phenoxy]-1-piperidyl]methyl]-2-phenyl-1H-benzimidazole

Procedure:

1) Synthesis of Compound (30) phenol, 2-[(tetrahydro-2H-pyran-2yl)oxy]

Catechol (2 g, 1 eq., 18.2 mmol) and dihydropyran (1.66 mL, 1 eq., 18.2mmol) were introduced to a solution of pyridinium p-toluenesulfonate (46mg, 1 mol %, 0.182 mmol) in DCM (35 mL). The solution was then stirredat room temperature for 3 hours, and the solvent were removed in vacuo.The resulted mixture was then dissolved in EtOAc, washed twice withNaHCO₃, once with brine, dried over MgSO₄. Compound (30) (3.30 g, 94%)was obtained as a light yellow oil.

2) Synthesis of Compound (31)2-[2-[(3-diethoxyphosphorylphenyl)-methoxy]phenoxy]tetrahydropyran

Compound (30) (665 mg, 1.1 eq., 3.43 mmol) was dissolved inN,N-dimethylformamide (10 mL) in a 10-20 mL microwave vial. To thissolution was added potassium carbonate (868 mg., 2 eq., 6.28 mmol),compound (28) (1 g, 1 eq., 3.14 mmol) and few crystals of sodium iodide(catalytic amount). The solution was then stirred for 20 min. at 80° C.under microwave irradiation. After evaporation of all volatiles, theresidue was purified by silica gel chromatography. Compound (31) wasobtained as a colorless oil (974 mg, 72%).

3) Synthesis of Compound (32)2-[2-[(3-diethoxyphosphorylphenyl)methoxy]-phenoxy]tetrahydropyran

To a solution of compound (31) (1.60 g, 1 eq., 3.6 mmol) in ethanol (37mL) was added pyridium p-toluenesulfonate (45 mg, 5 mol %, 0.18 mmol).The solution was then stirred at 55° C. during 3 hours, followed by theevaporation of all volatiles. The residue was then purified by flashchromatography, eluting Petroleum Ether/ethyl acetate 65:35 to 1:1.Compound (32) was obtained as a light brown oil (1.28 g, quantitativeyield).

4) Synthesis of Compound (33)1-(tert-butoxycarbonyl)-4-hydroxypiperidine

tert-butyl 4-oxopiperidine-1-carboxylate (5 g, 1 eq., 25.1 mmol) wasdissolved in methanol (50 mL) under inert atmosphere. This solution wascooled down at 0° C., and sodium borohydride was subsequently addedportionwise (950 mg, 1 eq., 25.1 mmol). The solution was allowed toreach room temperature and was stirred for 20 h. The solution wascarefully quenched at 0° C. with 2N sodium hydroxide (20 mL), followedby evaporation of all volatiles. The mixture was then dissolved in ethylacetate (40 mL) and water (20 mL), the aqueous phase was extracted threetimes with ethyl acetate (3×40 mL), the organic phase was washed withH₂O (20 mL), brine (20 mL), dried over MgSO₄ and concentrated underreduced pressure. The resulting mixture was purified by silica gelcolumn chromatography (Petroleum Ether/EtOAc 8:2) to afforded compound(33) as a white solid (4.8 g, 95%).

5) Synthesis of Compound (34)1-(tert-butoxycarbonyl)-4-(p-toluensulfonyloxy)-piperidine

To a solution of compound (33) (5 g, 1 eq., 24.8 mmol) indichloromethane (50 mL) was added triethylamine (13.9 mL, 4 eq., 99.4mmol) and p-toluenesulfonyl chloride (9.47 g, 2 eq., 49.7 mmol). Thesolution was stirred for 20 h at room temperature followed by theconcentration of this solution in vacuo. The residue was then dissolvedin dichloromethane (20 mL) and water (20 mL), extracted with DCM (20mL), washed with 1N HCl (40 mL), extracted twice with DCM (2×40 mL),dried over MgSO₄ and evaporated. The resulting mixture was then purifiedby silica gel column chromatography (Petroleum ether/EtOAc 8:2) andcompound (34) was obtained as a white crystalline solid (8.7 g,quantitative yield).

6) Synthesis of Compound (35) tert-butyl4-[2-[(3-diethoxyphosphorylphenyl)-methoxy]phenoxy]piperidine-1-carboxylate

In a 2-5 mL microwave vial, compound (32) (100 mg, 1 eq., 0.29 mmol) wasdissolved in dimethylacetamide (DMA, 2.5 mL). To this mixture was addedpotassium carbonate (81 mg, 2 eq., 0.57 mmol) and compound (34) (152 mg,1.5 eq., 0.43 mmol), before being stirred at 140° C. during 30 min undermicrowave irradiation. The resulting residue was dissolved in ethylacetate (10 mL) and water (5 mL), and the aqueous phase was extractedthrice with ethyl acetate (3×10 mL). The organic phase was then washed 5times with water (5×5 mL), once with brine (5 mL) and dried overmagnesium sulfate. The residue was concentrated under reduced pressureand purified by silica gel column chromatography, elutingdichloromethane/methanol 99:1, to afford compound (35) as colorless oil(100 mg, 71%).

7) Synthesis of Compound (36)4-[2-[(3-diethoxyphosphorylphenyl)methoxy]-phenoxy]piperidine

Following general procedure 11, trifluoroacetic acid (1.5 mL, 100 eq.,19.7 mmol) was added to a solution of compound (35) (105 mg, 1 eq.,0.197 mmol) in dichloromethane (3 mL). Pure compound (36) was obtainedafter flash column chromatography (DCM/MeOH 95:5), affording desiredproduct as an orange solid (58 mg, 68%).

8) Synthesis of Compound (E61)

The title compound (E61) was obtained following the general procedure 12from compound (3) (22 mg, 1 eq., 0.099 mmol), SOCl₂ (210 μL, 29 eq.,2.87 mmol), compound (36) (43 mg, 1 eq., 0.099 mmol), anddiisopropylethylamine (90 μL, 5.3 eq., 0.53 mmol) in acetonitrile (3mL). After purification by silica gel column chromatography, elutingdichloromethane/methanol 95:5, the clean compound (E61) was obtained asan amorphous creamy solid. (24 mg, 38%)

Characterization:

¹H NMR: (400 MHz, MeOD) δ 8.09 (d, J=7.2 Hz, 2H, H^(Ar)), 7.57 (m, 5H,H^(Ar)), 7.33 (m, 5H, H^(Ar)), 7.03 (m, 2H, H^(Ar)), 6.91 (m, 2H,H^(Ar)), 5.06 (s, 2H, CH₂—O), 4.43 (s, 1H, H⁴ pip), 3.98 (ddq, J=8.0,7.0, 1.0 Hz, 4H, CH₂—O—P), 3.84 (s, 2H, CH₂—N), 3.23 (d, J=21.7 Hz, 2H,CH₂—P), 2.99 (bs, 2H, H², H⁶ pip), 2.62 (bs, 2H, H², H⁶ pip), 1.97 (m,4H, H³, H⁵ pip), 1.20 (td, J=7.0, 1.0 Hz, 6H, CH₃).

¹³C NMR: (101 MHz, MeOD) δ 152.28 (C^(quat)), 150.16 (C^(quat)), 147.08(C^(quat)), 137.88 (d, J=3.3 Hz, C^(quat)) 131.61 (d, J=9.4 Hz,C^(quat)) 130.13 (C^(Ar)) 129.47 (C^(quat)) 129.13 (d, J=6.6 Hz, C^(Ar))128.78 (C^(Ar)), 128.73 (d, J=7.0 Hz, C^(Ar)), 128.32 (d, J=3.4 Hz,C^(Ar)) 126.44 (C^(Ar)) 125.92 (d, J=3.7 Hz, C^(Ar)) 122.36 (C^(Ar))121.44 (C^(Ar)), 118.51 (C^(Ar)), 115.19 (C^(Ar)), 70.54 (CH₂—O), 62.35(d, J=6.9 Hz, CH₂—O—P), 62.21 (CH₂—N), 49.29 (C², C⁶ pip), 32.32 (d,J=137.7 Hz, CH₂—P), 29.41 (C3, C⁵ pip), 15.25 (d, J=6.0 Hz, CH₃).

³¹P NMR: (162 MHz, MeOD) δ 27.36.

HRMS-ESI (m/z) [M+H]⁺ calculated for C₃₇H₄₃N₃O₅P 640.2941, found640.2938.

Example 62: Synthesis of (E62)6-[[4-[2-[[3-(diethoxyphosphorylmethyl)phenyl]-methoxy]phenoxy]-1-piperidyl]methyl]-2-[4-(trifluoromethyl)phenyl]-1H-benzimidazole

Procedure:

The title compound (E62) was obtained following the general procedure 12from compound (12) (34 mg, 1 eq., 0.115 mmol), SOCl₂ (243 μL, 29 eq.,3.35 mmol), compound (36) (50 mg, 1 eq., 0.115 mmol) anddiisopropylethylamine (100 μL, 5.3 eq., 0.59 mmol) in acetonitrile (3mL). After purification by silica gel column chromatography, elutingdichloromethane/methanol 95:5, the title compound (E62) was obtained asan amorphous creamy solid. (19 mg, 22%)

Characterization:

¹H NMR: (400 MHz, MeOD) δ 8.45 (bs, 1H, H^(Ar)), 8.36 (d, J=7.8 Hz, 1H,H^(Ar)), 7.83 (n, 1H, H^(Ar)), 7.78 (m, 1H, H^(Ar)), 7.63 (m, 2H,H^(Ar)), 7.42 (bs, 1H, H^(Ar)), 7.32 (m, 4H, H^(Ar)), 7.02 (m, 2H,H^(Ar)), 6.91 (m, 2H, H^(Ar)), 5.06 (s, 2H, CH₂—O), 4.42 (d, J=7.4 Hz,1H, H⁴ pip), 3.99 (m, 4H, CH₂—O—P), 3.80 (s, 2H, CH₂—N), 3.25 (d, J=21.7Hz, 2H, CH₂—P), 2.94 (bs, 2H, H², H⁶ pip), 2.55 (bs, 2H, H², H⁶ pip),1.96 (m, 4H, H³, H⁵ pip), 1.22 (t, J=7.1 Hz, 6H, CH₃).

¹³C NMR: (101 MHz, MeOD) δ 150.87 (C^(quat)), 150.11 (C^(quat)), 147.19(C^(quat)), 137.94 (d, J=3.0 Hz, C^(quat)) 131.58 (d, J=9.5 Hz,C^(quat)) 131.39 (C^(quat)), 131.06 (C^(quat)), 130.63 (C^(quat)) 129.83(C^(Ar)) 129.82 (C^(Ar)) 129.77 (C^(Ar)), 129.09 (d, J=6.8 Hz, C^(Ar)),128.71 (d, J=6.9 Hz, C^(Ar)), 128.30 (d, J=2.8 Hz, C^(Ar)) 126.40(C^(Ar)), 125.89 (d, J=3.7 Hz, C^(Ar)), 125.36 (C^(Ar)) 123.06 (C^(Ar))122.23 (C^(Ar)), 121.45 (C^(Ar)) 118.38 (C^(Ar)), 115.28 (C^(Ar)), 70.56(CH₂—O), 62.38 (CH₂—N), 62.34 (d, J=6.9 Hz, CH₂—O—P), 49.43 (C², C⁶pip), 32.28 (d, J=138.1 Hz, CH₂—P), 29.75 (C3, C⁵ pip), 15.26 (d, J=6.0Hz, CH₃).

³¹P NMR: (162 MHz, MeOD) δ 27.36.

¹⁹F NMR: (376 MHz, MeOD) δ −64.31.

HRMS-ESI (m/z) [M+H]⁺ calculated for C₃₉H₄₂F₃N₃O₅P 708.2811, found708.2808.

Example 63: Synthesis of (E63)6-[[4-[2-[[3-(diethoxyphosphorylmethyl)phenyl]-methoxy]phenoxy]-1-piperidyl]methyl]-2-[3-(trifluoromethyl)phenyl]-1H-benzimidazole

Procedure:

The title compound (E63) was obtained following the general procedure 12from compound (14) (34 mg, 1 eq., 0.115 mmol), SOCl₂ (243 μL, 29 eq.,3.35 mmol), compound (36) (50 mg, 1 eq., 0.115 mmol), anddiisopropylethylamine (100 μL, 5.3 eq., 0.59 mmol) in acetonitrile (3mL). After purification by silica gel column chromatography, elutingdichloromethane/methanol 95:5, the clean compound (E63) was obtained asan amorphous creamy solid (20 mg, 24%).

Characterization:

¹H NMR: (400 MHz, MeOD) δ 8.40 (bs, 1H, H^(Ar)), 8.31 (d, J=7.9 Hz, 1H,H^(Ar)), 7.67 (n, 4H, H^(Ar)), 7.28 (m, 5H, H^(Ar)), 6.90 (m, 4H,H^(Ar)), 5.01 (s, 2H, CH₂—O), 4.36 (s, 1H, H⁴ pip), 3.94 (ddq, J=8.0,7.1, 1.0 Hz, 4H, CH₂—O—P), 3.71 (s, 2H, CH₂—N), 3.19 (d, J=21.7 Hz, 2H,CH₂—P), 2.86 (s, 2H, H², H⁶ pip), 2.44 (d, J=8.7 Hz, 2H, H², H⁶ pip),1.91 (dd, J=12.9, 8.4 Hz, 4H, H³, H⁵ pip), 1.16 (dt, J=7.1, 1.0 Hz, 6H,CH₃).

¹³C NMR: (101 MHz, MeOD) δ 150.79 (C^(quat)), 150.07 (C^(quat)), 147.25(C^(quat)), 137.94 (d, J=3.2 Hz, C^(quat)) 131.57 (d, J=9.4 Hz,C^(quat)) 131.38 (C^(quat)), 131.06 (C^(quat)), 130.65 (C^(quat)) 129.81(C^(Ar)) 129.79 (C^(Ar)), 129.07 (d, J=6.7 Hz, C^(Ar)), 128.70 (d, J=6.7Hz, C^(Ar)) 128.29 (d, J=3.1 Hz, C^(Ar)) 126.37 (C^(Ar)), 125.88 (d,J=3.6 Hz, C^(Ar)) 123.08 (C^(Ar)), 122.15 (C^(Ar)) 121.45 (C^(Ar))118.31 (C^(Ar)), 115.31 (C^(Ar)), 70.57 (CH₂—O), 62.53 (CH₂—N), 62.34(d, J=7.0 Hz, CH₂—O—P), 49.56 (C², C⁶ pip), 32.29 (d, J=137.6 Hz,CH₂—P), 29.89 (C3, C⁵ pip), 15.29, 15.26 (d, J=6.0 Hz, CH₃).

³¹P NMR: (162 MHz, MeOD) δ 27.36.

¹⁹F NMR: (376 MHz, MeOD) δ −64.31.

HRMS-ESI (m/z) [M+H]⁺ calculated for C₃₉H₄₂F₃N₃O₅P 708.2811, found708.2807.

Example 64: Synthesis of (E64)6-[[4-[2-[[3-(diethoxyphosphorylmethyl)phenyl]-methoxy]phenoxy]-1-piperidyl]methyl]-2-[4-(trifluoromethoxy)phenyl]-1H-benzimidazole

Procedure:

1. Synthesis of Compound (37) methyl2-[4-(trifluoromethoxy)phenyl]-3H-benzimidazole-5-carboxylate

The title compound was prepared from 4-trifluoromethoxybenzaldehyde(0.75 mL, 1 eq., 5.3 mmol), in presence of 40% NaHSO₃ (5.4 mL), methyl3,4-diaminobenzoate (881 mg, 1 eq., 5.3 mmol) and ethanol (3 mL)following the general procedure 4. Compound (37) (1.38 g, 78%) wasobtained as a light yellow solid.

2. Synthesis of Compound (38)[2-[4-(trifluoromethoxy)phenyl]-3H-benzimidazol-5-yl]methanol

Compound (38) was prepared following general procedure 5, starting fromcompound (37) (1.38 g, 1 eq., 4.11 mmol), LiAlH₄ (312 mg, 2 eq., 8.22mmol) in tetrahydrofuran (21 mL).

The product was isolated under the form of a white solid (1.21 g, 95%).

3. Synthesis of Compound (E64)

The title compound (E64) was obtained following the general procedure 12from benzimidazole (38) (37 mg, 1 eq., 0.12 mmol), SOCl₂ (246 μL, 29eq., 3.34 mmol), compound (36) (50 mg, 1 eq., 0.12 mmol), anddiisopropylethylamine (104 μL, 5.3 eq., 0.64 mmol) in AcN (3 mL). Afterpurification by silica gel column chromatography, elutingdichloromethane/methanol 95:5 of the resulting solution, the titlecompound (E64) was obtained as an amorphous creamy solid (19 mg, 31%).

Characterization:

¹H NMR: (400 MHz, MeOD) δ 8.20 (d, J=8.8 Hz, 2H, H^(Ar)), 7.63 (s, 2H,H^(Ar)), 7.39 (m, 7H, H^(Ar)), 7.03 (m, 2H, H^(Ar)), 6.92 (m, 2H,H^(Ar)), 5.07 (s, 2H, CH₂—O), 4.44 (s, 1H, H⁴ pip), 3.99 (dqd, J=7.8,6.8, 3.0 Hz, 4H, CH₂—O—P), 3.83 (s, 2H, CH₂—N), 3.25 (d, J=21.6 Hz, 2H,CH₂—P), 2.98 (bs, 2H, H², H⁶ pip), 2.60 (bs, 2H, H², H⁶ pip), 2.06-1.84(m, 4H, H³, H⁵ pip), 1.22 (t, J=6.8 Hz, 6H, CH₃).

¹³C NMR: (101 MHz, MeOD) δ 151.43 (C^(quat)), 151.25 (C^(quat)), 150.14(C^(quat)), 147.14 (C^(quat)) 137.91 (d, J=3.3 Hz, C^(quat)) 131.60 (d,J=9.1 Hz, C^(quat)) 129.10 (d, J=6.4 Hz, C^(Ar)) 128.72 (d, J=6.5 Hz,C^(Ar)), 128.60 (C^(Ar)), 128.32 (C^(Ar)), 128.30 (d, J=2.7 Hz, C^(Ar)),125.90 (d, J=3.7 Hz, C^(Ar)), 122.31 (C^(Ar)), 121.45 (C^(Ar)), 121.20(C^(Ar)), 118.46 (C^(Ar)), 115.24 (C^(Ar)), 70.55 (CH₂—O), 62.35 (d,J=6.9 Hz, CH₂—O—P), 62.32 (CH₂—N), 49.34 (C², C⁶ pip), 32.32 (d, J=137.2Hz, CH₂—P), 29.57 (C³, C⁵ pip), 15.25 (d, J=6.1 Hz, CH₃).

³¹P NMR: (162 MHz, MeOD) δ 27.36.

¹⁹F NMR: (376 MHz, MeOD) δ −57.38.

HRMS-ESI (m/z) [M+H]⁺ calculated for C₃₉H₄₂F₃N₃O₆P 724.2760, found724.2755.

Example 65: Synthesis of (E65)6-[[4-[2-[[3-(diethoxyphosphorylmethyl)phenyl]-methoxy]phenoxy]-1-piperidyl]methyl]-2-[3-(trifluoromethoxy)phenyl]-1H-benzimidazole

Procedure:

1. Synthesis of Compound (39) methyl2-[3-(trifluoromethoxy)phenyl]-3H-benzimidazole-5-carboxylate

The title compound was prepared from 3-trifluoromethoxybenzaldehyde(0.75 mL, 1 eq., 5.3 mmol), in presence of 40% NaHSO₃ (5.4 mL), methyl3,4-diaminobenzoate (881 mg, 1 eq., 5.3 mmol) and ethanol (3 mL)following the general procedure 4. Compound (37) (1.61 g, 91%) wasobtained as a white solid.

2. Synthesis of Compound (40)[2-[3-(trifluoromethoxy)phenyl]-3H-benzimidazol-5-yl]methanol

Compound (40) was prepared following general procedure 5, starting fromcompound (39) (1.61 g, 1 eq., 4.80 mmol), LiAlH₄ (364 mg, 2 eq., 9.59mmol) in THE (24 mL). The title compound was obtained under the form ofa white solid (1.41 g, 95%).

3. Synthesis of Compound (E65)

The title compound (E65) was obtained following the general procedure 12from compound (40) (27 mg, 1 eq., 0.088 mmol), SOCl₂ (186 μL, 29 eq.,2.56 mmol), compound (36) (38 mg, 1 eq., 0.088 mmol), anddiisopropylethylamine (79 μL, 5.3 eq., 0.47 mmol) in acetonitrile (2mL). After purification by silica gel column chromatography, elutingdichloromethane/methanol 95:5 of the resulting solution, the titlecompound (E65) was obtained as an amorphous creamy solid (22 mg, 35%).

Characterization:

¹H NMR: (400 MHz, MeOD) δ 8.06 (ddd, J=7.90, 1.6, 1.0 Hz, 1H, H^(Ar)),8.01 (s, 1H, H^(Ar)) 7.61 (q, J=8.2 Hz, 3H, H^(Ar)), 7.33 (m, 6H,H^(Ar)), 6.98 (m, 2H, H^(Ar)), 6.88 (m, 2H, H^(Ar)), 5.01 (s, 2H,CH₂—O), 4.39 (s, 1H, H⁴ pip), 3.94 (dqd, J=8.2, 7.0, 1.1 Hz, 4H,CH₂—O—P), 3.80 (s, 2H, CH₂—N), 3.20 (d, J=21.7 Hz, 2H, CH₂—P), 2.95 (s,2H, H², H⁶ pip), 2.57 (s, 2H, H², H⁶ pip), 1.91 (s, 4H, H³, H⁵ pip),1.21-1.10 (dt, J=7.0, 0.4 Hz, 6H, CH₃).

¹³C NMR: (101 MHz, MeOD) δ 150.93 (C^(quat)), 150.15 (C^(quat)), 149.73(C^(quat)), 147.09 (C^(quat)) 137.88 (d, J=3.2 Hz, C^(quat)) 131.73(C^(Ar)), 131.61 (d, J=9.3 Hz, C^(quat)) 130.71 (C^(Quat)) 129.10 (d,J=6.5 Hz, C^(Ar)), 128.72 (d, J=6.7 Hz, C^(Ar)), 128.31 (d, J=3.2 Hz,C^(Ar)), 125.90 (d, J=3.6 Hz, C^(Ar)), 125.01 (C^(Ar)) 122.34 (C^(Ar))121.44 (C^(Ar)) 118.93 (C^(Ar)) 118.48 (C^(Ar)) 115.20 (C^(Ar)) 73.12(C⁴ pip), 70.53 (CH₂—O), 62.34 (d, J=6.9 Hz, CH₂—O—P), 62.17 (CH₂—N),49.24 (C², C⁶ pip), 32.33 (d, J=137.5 Hz, CH₂—P), 29.45 (C3, C⁵ pip),15.25 (d, J=6.0 Hz, CH₃).

³¹P NMR: (162 MHz, MeOD) δ 27.36

¹⁹F NMR: (376 MHz, MeOD) δ −59.38

HRMS-ESI (m/z) [M+H]⁺ calculated for C₃₉H₄₂F₃N₃O₆P 724.2760, found724.2757.

Example 66: Synthesis of (E66)6-[[4-[[2-[[3-(diethoxyphosphorylmethyl)phenyl]-methoxy]phenyl]methyl]-1-piperidyl]methyl]-2-phenyl-1H-benzimidazole

Procedure:

1. Synthesis of Compound (41): 2-benzyloxybromobenzene

To a solution of 2-bromophenol (1.34 mL, 1 eq., 11.6 mmol) indimethylformamide (20 mL), benzyl chloride (1.46 mL, 1.1 eq., 12.7 mmol)and potassium carbonate (3.19 g, 2 eq., 23.1 mmol) were added. Theresulting mixture was stirred for 12 h at 70° C. After evaporation ofall volatiles, the residue was dissolved in a mixture of ethyl acetate(80 mL) and water (40 mL). The aqueous phase was extracted three timeswith ethyl acetate (3×80 mL), the organic phase was washed three timeswith water (3×40 mL), three times with brine (3×40 mL), dried overmagnesium sulfate and concentrated under reduced pressure. After afiltration on silica gel, eluting petroleum ether/ethyl acetate 8:2 ofthe resulting mixture, the compound (41) was obtained as a colorless oil(3.1 g, quantitative yield).

2. Synthesis of Compound (42) tert-butyl4-[(2-benzyloxyphenyl)-hydroxymethyl]piperidine-1-carboxylate

Under argon atmosphere, compound (41) (3.36 g, 1.1 eq., 12.7 mmol) wasdissolved in tetrahydrofuran (THF) (19 mL) and cooled down at −78° C.After 10 minutes stirring, n-BuLi (2.5 M in hexane, 5.03 mL, 1.1 eq.12.7 mmol) was added dropwise to the solution and stirred for 30 min. at−78° C. A solution of 1-(tert-Butoxycarbonyl)-4-piperidinecarboxaldehyde(2.47 g, 1 eq., 11.6 mmol) in THE (19 mL) was then introduced bycannulation slowly into the flask. After 10 min at −78° C., the solutionwas then allowed to stir at room temperature for 3 hours and quenchedwith a slow addition of water (20 mL). The aqueous phase wassubsequently extracted three times with ethyl acetate (3×80 mL), driedover MgSO₄ and reduced in vacuo. The resulting product was then loadedonto a silica gel column and purified eluting Petroleum ether/EthylAcetate 8:2.

Compound (42) was obtained as colorless crystals (2.94 g, 65%).

3. Synthesis of Compound (43) tert-butyl4-[(2-hydroxyphenyl)methyl]piperidine-1-carboxylate

In an autoclave, compound (42) (1 g, 1 eq., 2.55 mmol) was dissolved inethyl acetate (43 mL). The solution and the atmosphere in the apparatuswere degassed with argon before the introduction of 10% Pd/C (500 mg).The solution and the atmosphere were again saturated with argon, thenthe autoclave was sealed and filled with H₂ until a pressure of 7 bars.The reaction was stirred for 24 h at room temperature, filtrated ontoCelite®, and the filtrate was evaporated, giving the title compound (43)as colorless crystals (587 mg, 79%).

4. Synthesis of Compound (44) tert-butyl4-[[2-[[3-(diethoxyphosphorylmethyl)-phenyl]methoxy]phenyl]methyl]piperidine-1-carboxylate

In a 2-5 mL microwave vial, compound (32) (331 mg, 1.5 eq., 1.03 mmol)was dissolved in dimethylacetamide (5 mL). To this mixture weresequentially added potassium carbonate (190 mg, 2 eq., 1.37 mol),compound (43) (200 mg, 1 eq., 0.69 mmol) and a catalytic amount ofsodium iodide (few crystals). The reaction mixture was stirred for 30min at 140° C. under microwave irradiation, and the obtained solutionwas dissolved in water (10 mL) and ethyl acetate (50 mL). The aqueousphase was then extracted three times with ethyl acetate (3×30 mL), andthe organic phase washed five times with water (5×10 mL), once withbrine (10 mL), dried over MgSO₄ and evaporated. The residue wasconsequently purified by column chromatography (DCM/MeOH 99:1) to affordthe title compound (44) compound as a colorless oil (330 mg, 91%).

5. Synthesis of Compound (45)4-[[2-[[3-(diethoxyphosphorylmethyl)-phenyl]methoxy]phenyl]methyl]piperidine

Following the general procedure 11, trifluoroacetic acid (4.5 mL, 100eq., 58.3 mmol) was added to a solution of compound (44) (310 mg, 1 eq.,0.58 mmol) in dichloromethane (DCM) (9 mL). The title compound (45) wasobtained after flash column chromatography (DCM/methanol 95:5), as acolorless oil (235 mg, 94%).

6. Synthesis of Compound (E66)

The title compound (E66) was obtained following the general procedure 12from compound (3) (26 mg, 1 eq., 0.12 mmol), SOCl₂ (246 μL, 29 eq., 3.37mmol), compound (45) (50 mg, 1 eq., 0.12 mmol), anddiisopropylethylamine (105 μL, 5.3 eq., 0.61 mmol) in acetonitrile (3mL). After purification by silica gel column chromatography, elutingdichloromethane/methanol 95:5, the title compound (E66) was obtained asan amorphous creamy solid (20 mg, 24%).

Characterization:

¹H NMR: (400 MHz, MeOD) δ 8.10 (dd, J=8.1, 2.7 Hz, 2H, H^(Ar)), 7.67 (s,1H, H^(Ar)), 7.62 (d, J=8.6 Hz, 1H, H^(Ar)), 7.54 (m, 3H, H^(Ar)), 7.42(s, 1H, H^(Ar)), 7.32 (m, 3H, H^(Ar)), 7.24 (m, 1H, H^(Ar)), 7.15 (dt,J=8.1, 1.6 Hz, 1H), 7.10 (dd, J=7.4, 1.6 Hz, 1H, H^(Ar)), 6.98 (d, J=7.8Hz, 1H, H^(Ar)), 6.86 (td, J=7.4, 0.8 Hz, 1H, H^(Ar)), 5.07 (s, 2H,CH₂—O), 3.96 (m, 6H, CH₂—O—P, CH₂—N), 3.24 (d, J=21.6 Hz, 2H, CH₂—P),3.18 (bd, J=11.6 Hz, 2H, H², H⁶ pip), 2.64 (d, J=6.7 Hz, 2H, CH₂), 2.47(s, 2H, H², H⁶ pip), 1.80 (m, 1H, H⁴ pip), 1.74 (bd, J=14.9 Hz, 2H, H³,H⁵ pip), 1.45 (bq, J=14.4 Hz, 2H, H³, H⁵ pip), 1.20 (t, J=7.1 Hz, 6H,CH₃).

¹³C NMR: (101 MHz, MeOD) δ 156.59 (C^(quat)—CH₂), 153.14 (C^(quat)),149.72 (d, J=2.0 Hz, C^(quat)), 138.00 (d, J=3.4 Hz, C^(quat)) 131.64(d, J=9.2 Hz, C^(quat)) 130.59 (C^(Ar)), 130.25 (C^(Ar)) 129.37(C^(Ar)), 129.04 (d, J=6.7 Hz, C^(Ar)) 128.82 (C^(Ar)), 128.43 (d, J=6.5Hz, C^(Ar)) 128.34 (d, J=3.2 Hz, C^(Ar)) 128.29 (C^(Ar)) 127.17(C^(Ar)), 126.50 (C^(Ar)), 125.72 (C^(Ar)), 125.62 (d, J=3.6 Hz, C^(Ar))120.31 (C^(Ar)), 111.65 (C^(Ar)), 69.23 (CH₂—O), 62.38 (d, J=6.9 Hz,CH₂—O—P), 61.80 (CH₂—N), 52.70 (C², C⁶ pip), 36.13 (CH₂), 35.38 (C4pip), 32.30 (d, J=137.8 Hz, CH₂—P), 30.07 (C3, C⁵ pip), 15.26 (d, J=6.0Hz, CH₃).

³¹P NMR: (162 MHz, MeOD) δ 27.27.

HRMS-ESI (m/z) [M+H]⁺ calcd for C₃₉H₄₇N₃O₃P 638.3146, found 638.3141.

Example 67: Synthesis of (E67)6-[[4-[[2-[[3-(diethoxyphosphorylmethyl)phenyl]-methoxy]phenyl]methyl]-1-piperidyl]methyl]-2-[4-(trifluoromethyl)phenyl]-1H-benzimidazole

Procedure:

The title compound (E67) was obtained following the general procedure 12from compound (12) (60 mg, 1 eq., 0.20 mmol), SOCl₂ (452 μL, 29 eq.,6.20 mmol), compound (45) (80 mg, 1 eq., 0.20 mmol), anddiisopropylethylamine (168 μL, 5.3 eq., 0.99 mmol) in acetonitrile (4mL). After purification by silica gel column chromatography, elutingdichloromethane/methanol 95:5, the title compound (E67) was obtained asan amorphous creamy solid (24 mg, 19%).

Characterization:

¹H NMR: (400 MHz, MeOD) δ 8.46 (s, 1H, H^(Ar)), 8.37 (d, J=7.6 Hz, 1H,H^(Ar)), 7.75 (m, 4H, H^(Ar)), 7.33 (m, 5H, H^(Ar)), 7.14 (dd, J=7.8,1.8 Hz, 2H), 7.01 (dd, J=8.3, 1.1 Hz, 1H, H^(Ar)) 6.88 (td, J=7.4, 1.2Hz, 1H, H^(Ar)), 5.08 (s, 2H, CH₂—O), 4.26 (s, 2H, CH₂—N), 3.99 (dqd,J=9.5, 7.1, 1.5 Hz, 4H, CH₂—O—P), 3.38 (under MeOD peak, m, 2H, H², H⁶pip), 3.22 (under MeOD peak, m, 2H, CH₂—P), 2.81 (t, J=12.0 Hz, 2H, H²,H⁶ pip), 2.68 (d, J=6.8 Hz, 2H, CH₂), 1.90 (m, 1H, H⁴ pip), 1.82 (bd,J=13.5 Hz, 2H, H³, H⁵ pip), 1.55 (bt, J=12.0 Hz, 2H, H³, H⁵ pip), 1.21(td, J=7.1, 0.6 Hz, 6H, CH₃).

¹³C NMR: (101 MHz, MeOD) δ 156.60 (C^(quat)—CH₂), 151.84 (C^(quat)),137.93 (d, J=3.3 Hz, C^(quat)) 131.69 (d, J=9.3 Hz, C^(quat)) 131.56(C^(quat)), 130.57 (C^(Ar)) 130.36 (C^(Ar)) 129.94 (C^(Ar)) 129.90(C^(quat)), 129.10 (d, J=6.6 Hz, C^(Ar)), 128.45 (d, J=6.5 Hz, C^(Ar))128.34 (d, J=3.4 Hz, C^(Ar)) 127.88 (C^(Ar)), 127.35 (C^(Ar)), 125.68(d, J=3.9 Hz, C^(Ar)), 123.25 (C^(Ar)) 123.18 (C^(Ar)) 120.40 (C^(Ar))111.68 (C^(Ar)), 69.24 (CH₂—O), 62.41 (d, J=6.9 Hz, CH₂—O—P), 60.93(CH₂—N), 52.34 (C², C⁶ pip), 35.70 (CH₂), 34.86 (C4 pip), 32.16 (d,J=138.0 Hz, CH₂—P), 29.22 (C3, C⁵ pip), 15.24 (d, J=6.0 Hz, CH₃).

³¹P NMR: (162 MHz, MeOD) δ 27.22.

¹⁹F NMR: (376 MHz, MeOD) δ −64.36.

HRMS-ESI (m/z) [M+H]⁺ calculated for C₃₉H₄₄F₃N₃O₄P 706.3022, found706.3013.

Example 68: Synthesis of (E68)6-[[4-[[2-[[3-(diethoxyphosphorylmethyl)phenyl]-methoxy]phenyl]methyl]-1-piperidyl]methyl]-2-[3-(trifluoromethyl)phenyl]-1H-benzimidazole

Procedure:

The title compound (E68) was obtained following the general procedure 12from compound (14) (60 mg, 1 eq., 0.20 mmol), SOCl₂ (452 μL, 29 eq.,6.20 mmol,) compound (45) (80 mg, 1 eq., 0.20 mmol) anddiisopropylethylamine (168 μL, 5.3 eq., 0.99 mmol) in acetonitrile (4mL). After purification by silica gel column chromatography, elutingdichloromethane/methanol 95:5, the clean compound (E68) was obtained asan amorphous creamy solid (26 mg, 20%).

Characterization:

¹H NMR: (400 MHz, MeOD) δ 8.46 (s, 1H, H^(Ar)), 8.37 (d, J=7.8 Hz, 1H,H^(Ar)), 7.85 (d, J=7.8 Hz, 1H, H^(Ar)), 7.79 (t, J=7.8 Hz, 1H, H^(Ar)),7.68 (m, 2H, H^(Ar)), 7.44 (s, 1H, H^(Ar)), 7.35 (m, 3H, H^(Ar)), 7.27(m, 1H, H^(Ar)), 7.16 (dt, J=8.3, 1.8 Hz, 1H, H^(Ar)), 7.11 (dd, J=7.4,1.5 Hz, 1H, H^(Ar)), 6.99 (d, J=7.8 Hz, 1H, H^(Ar)), 6.87 (td, J=7.5,1.0 Hz, 1H, H^(Ar)), 5.09 (s, 2H, CH₂—O), 3.97 (m, 6H, CH₂—O—P, CH₂—N),3.26 (d, J=21.7 Hz, 2H, CH₂—P), 3.13 (bd, J=11.3 Hz, 2H, H², H⁶ pip),2.65 (d, J=6.8 Hz, 2H, CH₂), 2.38 (bs, 2H, H², H⁶ pip), 1.78 (m, 1H, H⁴pip), 1.73 (bd, J=13.4 Hz, 2H, H³, H⁵ pip), 1.44 (bq, J=13.4 Hz, 2H, H³,H⁵ pip), 1.22 (t, J=7.1 Hz, 6H, CH₃).

¹³C NMR: (101 MHz, MeOD) δ 156.59 (C^(quat)—CH₂), 151.20 (C^(quat)),138.03 (d, J=3.4 Hz, C^(quat)) 131.63 (d, J=9.1 Hz, C^(quat)) 131.42(C^(quat)) 131.10 (C^(quat)) 130.59 (C^(Ar)), 130.55 (C^(Ar)) 129.87(C^(Ar)) 129.83 (C^(Ar)), 129.02 (d, J=6.4 Hz, C^(Ar)) 128.46 (C^(Ar))128.37 (d, J=4.4 Hz, C^(Ar)), 128.33 (d, J=3.2 Hz, C^(Ar)) 127.09(C^(Ar)), 126.50 (C^(Ar)), 125.60 (d, J=3.8 Hz, C^(Ar)), 125.34(C^(Ar)), 123.12 (d, J=4.1 Hz, C^(Ar)) 122.64 (C^(Ar)) 120.26 (C^(Ar))111.64 (C^(Ar)) 69.22 (CH₂—O), 62.36 (d, J=7.0 Hz, CH₂—O—P), 62.12(CH₂—N), 52.87 (C², C⁶ pip), 36.33 (CH₂), 35.64 (C4 pip), 32.30 (d,J=137.2 Hz, CH₂—P), 30.46 (C3, C⁵ pip), 15.25 (d, J=5.9 Hz, CH₃).

³¹P NMR: (162 MHz, MeOD) δ 27.29.

¹⁹F NMR: (376 MHz, MeOD) δ −64.34.

HRMS-ESI (m/z) [M+H]⁺ calculated for C₃₉H₄₄F₃N₃O₄P 706.3022, found706.3013.

Example 69: Synthesis of (E69)6-[[4-[[2-[[3-(diethoxyphosphorylmethyl)phenyl]-methoxy]phenyl]methyl]-1-piperidyl]methyl]-2-[4-(trifluoromethoxy)phenyl]-1H-benzimidazole

Procedure:

The title compound (E69) was obtained following the general procedure 14from compound (38) (60 mg, 1 eq., 0.20 mmol), SOCl₂ (452 μL, 29 eq.,6.20 mmol), compound (45) (80 mg, 1 eq., 0.20 mmol), anddiisopropylethylamine (168 μL, 5.3 eq., 0.99 mmol) in acetonitrile (4mL). After purification by silica gel column chromatography, elutingdichloromethane/methanol 95:5 of the resulting mixture, the titlecompound (E69) was obtained as an amorphous creamy solid (31 mg, 24%).

Characterization:

¹H NMR: (400 MHz, MeOD) δ 8.21 (d, J=8.9 Hz, 2H, H^(Ar)), 7.67 (m, 2H,H^(Ar)), 7.49 (d, J=9.0 Hz, 2H, H^(Ar)), 7.44 (s, 1H, H^(Ar)), 7.31 (m,4H, H^(Ar)), 7.16 (dt, J=8.3, 1.5 Hz, 1H), 7.12 (dd, J=7.6, 1.6 Hz, 1H,H^(Ar)), 7.00 (d, J=8.3 Hz, 1H, H^(Ar)), 6.88 (td, J=7.5, 1.0 Hz, 1H,H^(Ar)), 5.10 (s, 2H, CH₂—O), 4.00 (m, 6H, CH₂—O—P, CH₂—N), 3.27 (d,J=21.8 Hz, 2H, CH₂—P), 3.18 (bd, J=11.8 Hz, 2H, H², H⁶ pip), 2.67 (d,J=6.8 Hz, 2H, CH₂), 2.47 (bs, 2H, H², H⁶ pip), 1.81 (m, 1H, H⁴ pip),1.75 (bd, J=15.4 Hz, 2H, H³, H⁵ pip), 1.46 (bq, J=10.4 Hz, 2H, H³, H⁵pip), 1.22 (t, J=7.1 Hz, 6H, CH₃).

¹³C NMR: (101 MHz, MeOD) δ 156.60 (C^(quat)—CH₂), 151.64 (C^(quat)),150.52 (C^(quat)), 138.00 (d, J=3.3 Hz, C^(quat)) 131.64 (d, J=9.2 Hz,C^(quat)) 130.59 (C^(Ar)), 129.03 (d, J=6.9 Hz, C^(Ar)) 128.50 (C^(Ar)),128.43 (d, J=6.6 Hz, C^(Ar)) 128.38 (C^(Ar)), 128.33 (d, J=3.1 Hz,C^(Ar)), 127.15 (C^(Ar)), 125.62 (d, J=3.7 Hz, C^(Ar)), 125.34 (C^(Ar)),123.12 (d, J=4.1 Hz, C^(Ar)) 121.74 (C^(Ar)) 121.25 (C^(Ar)) 120.29(C^(Ar)) 119.20 (C^(Ar)), 111.65 (C^(Ar)), 69.23 (CH₂—O), 62.38 (d,J=6.9 Hz, CH₂—O—P), 61.90 (CH₂—N), 52.87 (C², C⁶ pip), 36.20 (CH₂),35.45 (C4 pip), 32.26 (d, J=137.8 Hz, CH₂—P), 30.19 (C3, C⁵ pip), 15.25(d, J=6.0 Hz, CH₃)

³¹P NMR: (162 MHz, MeOD) δ 27.27

¹⁹F NMR: (376 MHz, MeOD) δ −59.39

HRMS-ESI (m/z) [M+H]⁺ calculated for C₃₉H₄₄F₃N₃O₅P 722.2971, found722.2965.

Example 70: Synthesis of (E70)6-[[4-[[2-[[3-(diethoxyphosphorylmethyl)phenyl]-methoxy]phenyl]methyl]-1-piperidyl]methyl]-2-[3-(trifluoromethoxy)phenyl]-3a,7a-dihydro-1H-benzimidazole

Procedure:

The title compound (E70) was obtained following the general procedure 12from benzimidazole (40) (60 mg, 1 eq., 0.20 mmol), SOCl₂ (452 μL, 29eq., 6.20 mmol) compound (45) (80 mg, 1 eq., 0.20 mmol) and thendiisopropylethylamine (168 μL, 5.3 eq., 0.99 mmol) in acetonitrile (4mL). After purification by silica gel column chromatography, elutingDCM/MeOH 95:5 of the resulting mixture, the title compound (E70) wasobtained as an amorphous creamy solid (26 mg, 20%).

Characterization:

¹H NMR: (400 MHz, MeOD) δ 8.10 (ddd, J=7.8, 1.3, 0.6 Hz, 1H, H^(Ar)),8.05 (s, 1H, H^(Ar)) 7.66 (m, 3H, H^(Ar)), 7.45 (m, 2H, H^(Ar)), 7.28(m, 4H, H^(Ar)), 7.14 (dt, J=7.4, 1.7 Hz, 1H), 7.10 (dd, J=7.7, 1.7 Hz,1H, H^(Ar)), 6.98 (d, J=8.0 Hz, 1H, H^(Ar)), 6.86 (td, J=7.4, 1.0 Hz,1H, H^(Ar)), 5.07 (s, 2H, CH₂—O), 3.98 (m, 6H, CH₂—O—P, CH₂—N), 3.25 (d,J=21.7 Hz, 2H, CH₂—P), 3.17 (bd, J=10.2 Hz, 2H, H², H⁶ pip), 2.64 (d,J=6.7 Hz, 2H, CH₂), 2.47 (bt, J=11.8 Hz, 2H, H², H⁶ pip), 1.81 (m, 1H,H⁴ pip), 1.74 (bd, J=13.0 Hz, 2H, H³, H⁵ pip), 1.45 (bq, J=13.3 Hz, 2H,H³, H⁵ pip), 1.20 (t, J=6.8 Hz, 6H, CH₃).

¹³C NMR: (101 MHz, MeOD) δ 156.58 (C^(quat)—CH₂), 151.29 (C^(quat)),149.72 (d, J=2.0 Hz, C^(quat)), 137.99 (d, J=3.3 Hz, C^(quat)) 131.63(C^(quat)), 131.61 (d, J=9.9 Hz, C^(quat)) 130.75 (C^(Ar)), 130.58(C^(Ar)), 129.02 (d, J=7.1 Hz, C^(Ar)), 128.41 (d, J=6.9 Hz, C^(Ar))128.36 (C^(Ar)) 128.34 (d, J=3.7 Hz, C^(Ar)), 127.15 (C^(Ar)), 125.61(d, J=3.7 Hz, C^(Ar)), 125.43 (C^(Ar)), 125.01 (C^(Ar)), 122.57(C^(Ar)), 122.46 (C^(Ar)), 120.30 (C^(Ar)), 120.29 (Ar), 118.97 (Ar),118.50 (C^(Ar)), 111.64 (C^(Ar)), 69.22 (CH₂—O), 62.36 (d, J=6.9 Hz,CH₂—O—P), 61.80 (CH₂—N), 52.70 (C², C⁶ pip), 36.14 (CH₂), 35.41 (C4pip), 32.23 (d, J=137.7 Hz, CH₂—P), 30.12 (C3, C⁵ pip), 15.25 (d, J=6.0Hz, CH₃)

³¹P NMR: (162 MHz, MeOD) δ 27.27

¹⁹F NMR: (376 MHz, MeOD) δ −59.39

HRMS-ESI (m/z) [M+H]⁺ calculated for C₃₉H₄₄F₃N₃O₅P 722.2971, found722.2964.

Example 71: Synthesis of (E71)6-[[4-[2-[[4-(diethoxyphosphorylmethyl)phenyl]-methoxy]phenoxy]-1-piperidyl]methyl]-2-phenyl-1H-benzimidazole

Procedure:

1. Synthesis of Compound (46)2-[2-[[4-(dimethoxyphosphorylmethyl)-phenyl]methoxy]phenoxy]tetrahydropyran

Compound (30) (1.12 g, 1 eq., 5.74 mmol) was dissolved indimethylformamide (18 mL) in a 10-20 mL microwave vial. To this solutionwas added potassium carbonate (1.58 g, 2 eq., 11.48 mmol), compound (26)(2.03 g, 1.1 eq., 6.32 mmol) and few crystals of sodium iodide(catalytic amount). The solution was then stirred for 20 min at 80° C.under microwave irradiation. After evaporation of all volatiles, theresidue was purified by silica gel chromatography to afford the titlecompound (46) as a colorless oil (1.42 g, 57%).

2. Synthesis of Compound (47)2-[[4-(dimethoxyphosphorylmethyl)-phenyl]methoxy]phenol

To a solution of compound (46) (1.16 g, 1 eq., 2.67 mmol) in ethanol (27mL) was added pyridium p-toluenesulfonate (34 mg, 5 mol %, 0.13 mmol).The solution was then stirred at 55° C. during 3 hours, followed by theevaporation of all volatiles. The residue was then purified by flashchromatography, eluting Petroleum Ether/EtOAc 65:35 to 1:1, to givecompound (47) as a white solid (936 mg, quantitative yield).

3. Synthesis of Compound (48) tert-butyl4-[2-[(4-diethoxyphosphorylphenyl)-methoxy]phenoxy]piperidine-1-carboxylate

In a 10-20 mL microwave vial, compound (47) (512 mg, 1 eq., 1.46 mmol)was dissolved in dimethylacetamide (13 mL). To this mixture was thenadded potassium carbonate (404 mg, 2 eq., 2.92 mmol) and compound (34)(778 mg, 1.5 eq., 2.19 mmol), before being stirred at 140° C. during 30min under microwave irradiation. The resulting residue was dissolved inethyl acetate (20 mL) and water (25 mL), and the aqueous phase wasextracted three times with ethyl acetate (3×20 mL). The organic phasewas then washed 5 times with water (5×25 mL), once with brine (25 mL)and dried over magnesium sulfate. The residue was concentrated underreduced pressure and purified by silica gel column chromatography,eluting dichloromethane/methanol 99:1, to afford the compound (48) ascolorless oil (483 mg, 62% of conversion).

4. Synthesis of Compound (49)4-[2-[(4-diethoxyphosphorylphenyl)-methoxy]phenoxy]piperidine

Following general procedure 11, trifluoroacetic acid (10.6 mL, 100 eq.,139 mmol) was added to a solution of compound (48) (740 mg, 1 eq., 1.39mmol) in dichloromethane (20 mL). Pure compound (49) was obtained afterflash column chromatography (dichloromethane/methanol 95:5), as anorange solid (588 mg, 67%).

5. Synthesis of Compound (E71)

The title compound (E71) was obtained following the general procedure 12from compound (3) (31 mg, 1 eq., 0.138 mmol), SOCl₂ (293 μL, 29 eq.,4.01 mmol), compound (49) (60 mg, 1 eq., 0.138 mmol), anddiisopropylethylamine (124 μL, 5.3 eq., 0.73 mmol) in acetonitrile (2mL). After purification by silica gel column chromatography, elutingdichloromethane/methanol 95:5, the title compound (E71) was obtained asan amorphous creamy solid (29 mg, 40%).

Characterization:

¹H NMR: (400 MHz, MeOD) δ 8.12 (d, J=7.0 Hz, 2H, H^(Ar)), 7.63 (m, 5H,H^(Ar)), 7.37 (m, 5H, H^(Ar)), 7.04 (m, 2H, H^(Ar)), 6.91 (dquint,J=7.3, 1.9 Hz, 2H, H^(Ar)), 5.06 (s, 2H, CH₂—O), 4.48 (s, 1H, H⁴ pip),4.00 (ddq, J=8.8, 7.0, 1.8 Hz, 4H, CH₂—O—P), 3.93 (s, 2H, CH₂—N), 3.24(d, J=21.7 Hz, 2H, CH₂—P), 3.06 (bs, 2H, H², H⁶ pip), 2.76 (bs, 2H, H²,H⁶ pip), 1.97 (m, 4H, H³, H⁵ pip), 1.23 (t, J=7.0 Hz, 6H, CH₃).

¹³C NMR: (101 MHz, MeOD) δ 150.15 (C^(quat)), 147.01 (C^(quat)), 136.24(d, J=3.9 Hz, C^(quat)) 131.11 (d, J=9.2 Hz, C^(quat)) 130.19 (C^(Ar)),129.71 (d, J=6.6 Hz, C^(Ar)) 129.42 (C^(Ar)) 128.79 (C^(Ar)) 127.59 (d,J=4.0 Hz, C^(Ar)) 126.48 (C^(Ar)) 122.46 (C^(Ar)) 121.46 (C^(Ar)),118.52 (C^(Ar)) 115.23 (C^(Ar)), 70.49 (CH₂—O), 62.30 (d, J=6.9 Hz,CH₂—O—P), 62.09 (CH₂—N), 48.99 (C², C⁶ pip), 32.00 (d, J=138.2 Hz,CH₂—P), 29.14 (C3, C⁵ pip), 15.23 (d, J=6.0 Hz, CH₃).

³¹P NMR: (162 MHz, MeOD) δ 27.43.

HRMS-ESI (m/z) [M+H]⁺ calculated for C₃₇H₄₃N₃O₅P 640.2941, found640.2935.

Example 72: Synthesis of (E72)6-[[4-[2-[[4-(diethoxyphosphorylmethyl)phenyl]-methoxy]phenoxy]-1-piperidyl]methyl]-2-[4-(trifluoromethyl)phenyl]-3a,7a-dihydro-1H-benzimidazole

Procedure:

The title compound (E72) was obtained following the general procedure 12from compound (12) (34 mg, 1 eq., 0.115 mmol), SOCl₂ (243 μL, 29 eq.,3.35 mmol), compound (49) (50 mg, 1 eq., 0.115 mmol), anddiisopropylethylamine (100 μL, 5.3 eq., 0.59 mmol) in acetonitrile (3mL). After purification by silica gel column chromatography, elutingdichloromethane/methanol 95:5, the clean compound (E72) was obtained asan amorphous creamy solid (28 mg, 32%).

Characterization:

¹H NMR: (400 MHz, MeOD) δ 8.42 (bs, 1H, H^(Ar)), 8.33 (d, J=8.0 Hz, 1H,H^(Ar)), 7.70 (m, 5H, H^(Ar)), 7.38 (d, J=8.0 Hz, 2H, H^(Ar)), 7.28 (m,3H, H^(Ar)), 6.98 (m, 2H, H^(Ar)), 6.88 (m, 2H, H^(Ar)), 5.01 (s, 2H,CH₂—O), 4.37 (d, J=7.4 Hz, 1H, H⁴ pip), 3.98 (m, 4H, CH₂—O—P), 3.75 (s,2H, CH₂—N), 3.20 (d, J=21.8 Hz, 2H, CH₂—P), 2.89 (bs, 2H, H², H⁶ pip),2.51 (bs, 2H, H², H⁶ pip), 1.89 (m, 4H, H³, H⁵ pip), 1.20 (t, J=7.1 Hz,6H, CH₃).

¹³C NMR: (101 MHz, MeOD) δ 150.89 (C^(quat)), 150.05 (C^(quat)), 147.19(C^(quat)), 136.29 (d, J=3.0 Hz, C^(quat)) 131.36 (C^(quat)), 131.04(C^(quat)) 130.94 (C^(quat)), 130.72 (C^(quat)), 130.63 (C^(quat))129.83 (C^(Ar)) 129.78 (C^(Ar)), 129.67 (d, J=6.6 Hz, C^(Ar)), 127.50(d, J=3.3 Hz, C^(Ar)) 126.38 (C^(Ar)) 125.36 (C^(Ar)), 125.14 (C^(Ar))123.08 (C^(Ar)) 122.66 (C^(Ar)) 122.19 (C^(Ar)), 121.45 (C^(Ar)) 118.29(C^(Ar)), 115.33 (C^(Ar)), 70.50 (CH₂—O), 62.48 (CH₂—N), 62.30 (d, J=7.0Hz, CH₂—O—P), 49.37 (C², C⁶ pip), 31.96 (d, J=138.1 Hz, CH₂—P), 29.70(C3, C⁵ pip), 15.25 (d, J=5.9 Hz, CH₃).

³¹P NMR: (162 MHz, MeOD) δ 27.42.

¹⁹F NMR: (376 MHz, MeOD) δ −64.25.

HRMS-ESI (m/z) [M+H]⁺ calculated for C₃₉H₄₂F₃N₃O₅P 708.2811, found708.2812.

Example 73: Synthesis of (E73)6-[[4-[2-[[4-(diethoxyphosphorylmethyl)phenyl]-methoxy]phenoxy]-1-piperidyl]methyl]-2-[3-(trifluoromethyl)phenyl]-1H-benzimidazole

Procedure:

The title compound (E73) was obtained following the general procedure 12from compound (14) (47 mg, 1 eq., 0.16 mmol), SOCl₂ (340 μL, 29 eq.,4.68 mmol), compound (49) (70 mg, 1 eq., 0.16 mmol), anddiisopropylethylamine (144 μL, 5.3 eq., 0.85 mmol) in acetonitrile (4mL). After purification by silica gel column chromatography, elutingdichloromethane/methanol 95:5, the compound (E73) was obtained as anamorphous creamy solid.

Characterization:

¹H NMR: (400 MHz, MeOD) δ 8.42 (bs, 1H, H^(Ar)), 8.33 (d, J=8.0 Hz, 1H,H^(Ar)), 7.71 (m, 5H, H^(Ar)), 7.38 (d, J=8.0 Hz, 2H, H^(Ar)), 7.28 (m,3H, H^(Ar)), 6.99 (m, 2H, H^(Ar)), 6.87 (m, 2H, H^(Ar)), 5.02 (s, 2H,CH₂—O), 4.40 (s, 1H, H⁴ pip), 3.96 (m, 4H, CH₂—O—P), 3.85 (s, 2H,CH₂—N), 3.19 (d, J=23.3 Hz, 2H, CH₂—P), 2.97 (bs, 2H, H², H⁶ pip), 2.68(bs, 2H, H², H⁶ pip), 1.95 (m, 4H, H³, H⁵ pip), 1.18 (t, J=6.9 Hz, 6H,CH₃).

HRMS-ESI (m/z) [M+H]⁺ calculated for C₃₉H₄₂F₃N₃O₅P 708.2811, found708.2809.

Example 74: Synthesis of (E74)6-[[4-[2-[[4-(diethoxyphosphorylmethyl)phenyl]-methoxy]phenoxy]-1-piperidyl]methyl]-2-[4-(trifluoromethoxy)phenyl]-1H-benzimidazole

Procedure:

The title compound (E74) was obtained following the general procedure 12from compound (38) (36 mg, 1 eq., 0.12 mmol), SOCl₂ (244 μL, 29 eq.,3.35 mmol), compound (49) (50 mg, 1 eq., 0.12 mmol), anddiisopropylethylamine (104 μL, 5.3 eq., 0.61 mmol) in acetonitrile (2mL). After purification by silica gel column chromatography, elutingdichloromethane/methanol 95:5, the compound (E74) was obtained as anamorphous creamy solid (17 mg, 23%).

Characterization:

¹H NMR: (400 MHz, MeOD) δ 8.17 (d, J=9.0 Hz, 2H, H^(Ar)), 7.61 (m, 2H,H^(Ar)), 7.46 (d, J=8.7 Hz, 2H, H^(Ar)), 7.39 (d, J=7.8 Hz, 2H, H^(Ar)),7.30 (m, 3H, H^(Ar)), 6.99 (m, 2H, H^(Ar)), 6.89 (m, 2H, H^(Ar)), 5.02(s, 2H, CH₂—O), 4.40 (s, 1H, H⁴ pip), 3.99 (dqd, J=9.8, 7.0, 1.6 Hz, 4H,CH₂—O—P), 3.80 (s, 2H, CH₂—N), 3.21 (d, J=21.9 Hz, 2H, CH₂—P), 2.95 (bs,2H, H², H⁶ pip), 2.58 (bs, 2H, H², H⁶ pip), 1.92 (m, 4H, H³, H⁵ pip),1.21 (t, J=7.1 Hz, 6H, CH₃).

¹³C NMR: (101 MHz, MeOD) δ 151.27 (C^(quat)), 150.42 (C^(quat)), 150.08(C^(quat)), 147.13 (C^(quat)) 136.27 (d, J=4.0 Hz, C^(quat)) 131.00 (d,J=9.2 Hz, C^(quat)) 129.68 (d, J=6.7 Hz, C^(Ar)) 128.59 (C^(Ar)) 128.33(C^(Ar)), 127.53 (d, J=2.7 Hz, C^(Ar)), 125.04 (C^(Ar)) 122.29 (C^(Ar))121.74 (C^(Ar)), 121.45 (C^(Ar)) 121.18 (C^(Ar)) 118.37 (C^(Ar)), 115.30(C^(Ar)), 70.50 (CH₂—O), 62.30 (d, J=6.9 Hz, CH₂—O—P), 62.30 (CH₂—N),49.20 (C², C⁶ pip), 31.96 (d, J=137.2 Hz, CH₂—P), 29.49 (C3, C⁵ pip),15.24 (d, J=6.0 Hz, CH₃).

³¹P NMR: (162 MHz, MeOD) δ 27.43.

¹⁹F NMR: (376 MHz, MeOD) δ −59.34.

HRMS-ESI (m/z) [M+H]⁺ calculated for C₃₉H₄₂F₃N₃O₆P 724.2760, found724.2757.

Example 75: Synthesis of (E75)6-[[4-[2-[[4-(diethoxyphosphorylmethyl)phenyl]-methoxy]phenoxy]-1-piperidyl]methyl]-2-[3-(trifluoromethoxy)phenyl]-1H-benzimidazole

Procedure:

The title compound (E75) was obtained following the general procedure 4from compound (40) (36 mg, 1 eq., 0.12 mmol), SOCl₂ (244 μL, 29 eq.,3.35 mmol), compound (49) (50 mg, 1 eq., 0.12 mmol), anddiisopropylethylamine (104 μL, 5.3 eq., 0.61 mmol) in acetonitrile (2mL). After purification by silica gel column chromatography, elutingdichloromethane/methanol 95:5, the compound (E75) was obtained as anamorphous creamy solid (18 mg, 25%).

Characterization:

¹H NMR: (400 MHz, MeOD) δ 8.08 (d, J=8.0 Hz, 1H, H^(Ar)), 8.03 (s, 1H,H^(Ar)), 7.62 (m, 3H, H^(Ar)), 7.41 (m, 3H, H^(Ar)), 7.31 (m, 3H,H^(Ar)), 6.99 (m, 2H, H^(Ar)), 6.88 (m, 2H, H^(Ar)), 5.02 (s, 2H,CH₂—O), 4.39 (s, 1H, H⁴ pip), 3.99 (dqd, J=8.0, 7.0, 1.6 Hz, 4H,CH₂—O—P), 3.77 (s, 2H, CH₂—N), 3.21 (d, J=21.7 Hz, 2H, CH₂—P), 2.91 (s,2H, H², H⁶ pip), 2.54 (s, 2H, H², H⁶ pip), 1.91 (s, 4H, H³, H⁵ pip),1.21 (dt, J=7.0, 0.4 Hz, 6H, CH₃).

¹³C NMR: (101 MHz, MeOD) δ 150.88 (C^(quat)), 150.06 (C^(quat)), 149.71(d, J=2.0 Hz, 1H, H^(Ar)), 147.15 (C^(quat)) 136.29 (d, J=3.9 Hz,C^(quat)) 131.78 (C^(Ar)), 131.00 (d, J=9.5 Hz, C^(quat)) 130.69(C^(Quat)), 129.66 (d, J=6.7 Hz, C^(Ar)), 127.51 (d, J=3.2 Hz, C^(Ar)),125.01 (C^(Ar)) 122.29 (C^(Ar)) 122.21 (C^(Ar)) 121.82 (Ar), 121.45(C^(Ar)) 119.27 (C^(Ar)) 118.92 (C^(Ar)) 118.31 (C^(Ar)) 115.33(C^(Ar)), 70.50 (CH₂—O), 62.43 (CH₂—N), 62.31 (d, J=7.0 Hz, CH₂—O—P),49.34 (C², C⁶ pip), 32.02 (d, J=138.0 Hz, CH₂—P), 29.67 (C3, C⁵ pip),15.24 (d, J=6.0 Hz, CH₃).

³¹P NMR: (162 MHz, MeOD) δ 27.43.

¹⁹F NMR: (376 MHz, MeOD) δ −59.35.

HRMS-ESI (m/z) [M+H]⁺ calculated for C₃₉H₄₂F₃N₃O₆P 724.2760, found724.2759.

Example 76: Synthesis of (E76)6-[[4-[[2-[[4-(diethoxyphosphorylmethyl)phenyl]-methoxy]phenyl]methyl]-1-piperidyl]methyl]-2-phenyl-1H-benzimidazole

Procedure:

1. Synthesis of Compound (50) tert-butyl4-[[2-[[4-(diethoxyphosphorylmethyl)phenyl]-methoxy]phenyl]methyl]piperidine-1-carboxylate

In a 10-20 mL microwave vial, compound (26) (1.32 mg, 1.5 eq., 4.12mmol) was dissolved in DMA (20 mL). To this mixture were sequentiallyadded potassium carbonate (760 mg, 2 eq., 5.49 mol), compound (43) (800mg, 1 eq., 2.45 mmol) and a catalytic amount of sodium iodide (fewcrystals). This reaction was stirred for 30 min at 140° C. undermicrowave irradiation, and the obtained solution was dissolved in water(20 mL) and diethyl ether (100 mL). The aqueous phase was then extractedtwice ethyl acetate (2×50 mL), and the organic phase washed 5 times withwater (5×40 mL), once with brine (40 mL), dried over MgSO₄ andevaporated. The residue was consequently purified by columnchromatography (dichloromethane/methanol 99:1) to afford compound (50)as a white solid (920 mg, 71% of conversion).

2. Synthesis of Compound (51)4-[[2-[[4-(diethoxyphosphorylmethyl)phenyl]-methoxy]phenyl]methyl]piperidine

Following general procedure 11, trifluoroacetic acid (7.2 mL, 100 eq.,94.0 mmol) was added to a solution of compound (50) (500 mg, 1 eq., 0.94mmol) in dichloromethane (15 mL). Pure compound (51) was obtained afterflash column chromatography (dichloromethane/ethanol 95:5), and compound(52) was obtained as a light brown solid (356 mg, 88%).

3. Synthesis of Compound (E76)

The title compound (E76) was obtained following the general procedure 12from compound (3) (26 mg, 1 eq., 0.12 mmol), SOCl₂ (246 μL, 29 eq., 3.37mmol), compound (51) (50 mg, 1 eq., 0.12 mmol), anddiisopropylethylamine (105 μL, 5.3 eq., 0.61 mmol) in acetonitrile (3mL). After purification by silica gel column chromatography, elutingdichloromethane/methanol 95:5, the title compound (E76) was obtained asan amorphous creamy solid (13 mg, 18%).

Characterization:

¹H NMR: (400 MHz, MeOD) δ 8.11 (dd, J=8.0, 2.0 Hz, 2H, H^(Ar)), 7.65 (m,2H, H^(Ar)), 7.57 (m, 3H, H^(Ar)), 7.42 (d, J=7.8 Hz, 2H, H^(Ar)), 7.33(m, 3H, H^(Ar)), 7.16 (dt, J=8.4, 1.6 Hz, 1H), 7.10 (dd, J=7.3, 1.6 Hz,1H, H^(Ar)), 6.98 (d, J=8.4 Hz, 1H, H^(Ar)), 6.86 (t, J=7.4 Hz, 1H,H^(Ar)), 5.08 (s, 2H, CH₂—O), 4.02 (m, 6H, CH₂—O—P, CH₂—N), 3.25 (d,J=21.2 Hz, 2H, CH₂—P), 3.18 (bd, J=12.1 Hz, 2H, H², H⁶ pip), 2.64 (d,J=6.7 Hz, 2H, CH₂), 2.47 (bs, 2H, H², H⁶ pip), 1.82 (m, 1H, H⁴ pip),1.74 (bd, J=14.5 Hz, 2H, H³, H⁵ pip), 1.45 (dq, J=11.2, 2.7 Hz, 2H, H³,H⁵ pip), 1.24 (t, J=7.1 Hz, 6H, CH₃).

¹³C NMR: (101 MHz, MeOD) δ 156.62 (C^(quat)—CH₂), 153.11 (C^(quat)),136.42 (d, J=4.3 Hz, C^(quat)) 130.93 (d, J=9.2 Hz, C^(quat)) 130.57(C^(Ar)) 130.24 (C^(Ar)), 129.72 (d, J=6.4 Hz, C^(Ar)) 129.38 (C^(Ar))128.81 (C^(Ar)) 128.30 (C^(Ar)), 127.26 (d, J=3.2 Hz, C^(Ar)) 128.29(C^(Ar)) 127.13 (C^(Ar)) 126.49 (C^(Ar)), 120.25 (C^(Ar)) 111.74(C^(Ar)), 69.26 (CH₂—O), 62.30 (d, J=7.3 Hz, CH₂—O—P), 61.89 (CH₂—N),52.69 (C², C⁶ pip), 36.24 (CH₂), 35.25 (C⁴ pip), 31.88 (d, J=138.1 Hz,CH₂—P), 30.13 (C³, C⁵ pip), 15.24 (d, J=6.0 Hz, CH₃).

³¹P NMR: (162 MHz, MeOD) δ 27.27.

HRMS-ESI (m/z) [M+H]⁺ calculated for C₃₉H₄₇N₃O₃P 638.3146, found638.3144.

Example 77: Synthesis of (E77)6-[[4-[[2-[[4-(diethoxyphosphorylmethyl)phenyl]-methoxy]phenyl]methyl]-1-piperidyl]methyl]-2-[4-(trifluoromethyl)phenyl]-1H-benzimidazole

Procedure:

The title compound (E77) was obtained following the general procedure 12from compound (12) (41 mg, 1 eq., 0.14 mmol), SOCl₂ (296 μL, 29 eq.,4.06 mmol), compound (51) (60 mg, 1 eq., 0.14 mmol), anddiisopropylethylamine (116 μL, 5.3 eq., 0.70 mmol) in acetonitrile (3mL). After purification by silica gel column chromatography, elutingdichloromethane/methanol 95:5, the compound (E77) was obtained as anamorphous creamy solid (13 mg, 15%).

Characterization:

¹H NMR: (250 MHz, MeOD) δ 8.45 (s, 1H, H^(Ar)), 8.36 (d, J=7.6 Hz, 1H,H^(Ar)), 7.75 (m, 4H, H^(Ar)), 7.35 (m, 5H, H^(Ar)), 7.10 (m, 2H,H^(Ar)), 6.96 (dd, J=8.2, 0.9 Hz, 1H, H^(Ar)), 6.83 (dt, J=7.2, 1.0 Hz,1H, H^(Ar)), 5.04 (s, 2H, CH₂—O), 4.35 (s, 2H, CH₂—N), 3.99 (dqd, J=8.6,7.1, 0.5 Hz, 4H, CH₂—O—P), 3.39 (bd, J=12.0 Hz, 2H, H², H⁶ pip), 3.21(d, J=21.6 Hz, 2H, CH₂—P), 2.92 (bt, J=12.0 Hz, 2H, H², H⁶ pip), 2.63(d, J=6.2 Hz, 2H, CH₂), 1.92 (m, 1H, H⁴ pip), 1.81 (bd, J=14.7 Hz, 2H,H³, H⁵ pip), 1.55 (m, 2H, H³, H⁵ pip), 1.20 (td, J=7.0, 0.5 Hz, 6H,CH₃).

HRMS-ESI (m/z) [M+H]⁺ calculated for C₃₉H₄₄F₃N₃O₄P 706.3022, found706.3017.

Example 78: Synthesis of (E78)6-[[4-[[2-[[4-(diethoxyphosphorylmethyl)phenyl]methoxy]phenyl]methyl]-1-piperidyl]methyl]-2-[3-(trifluoromethyl)phenyl]-1H-benzimidazole

Procedure:

The title compound (E78) was obtained following the general procedure 12from benzimidazole (14) (41 mg, 1 eq., 0.14 mmol), SOCl₂ (296 μL, 29eq., 4.06 mmol,) compound (51) (60 mg, 1 eq., 0.14 mmol), anddiisopropylethylamine (116 μL, 5.3 eq., 0.70 mmol) in acetonitrile (3mL). After purification by silica gel column chromatography, elutingdichloromethane/methanol 95:5, the title compound (E78) was obtained asan amorphous creamy solid (16 mg, 18%).

Characterization:

¹H NMR: (250 MHz, MeOD) δ 8.44 (s, 1H, H^(Ar)), 8.36 (d, J=8.8 Hz, 1H,H^(Ar)), 7.96 (s, 1H, H^(Ar)), 7.75 (m, 5H, H^(Ar)), 7.53 (d, J=7.5 Hz,1H, H^(Ar)), 7.44 (s, 1H, H^(Ar)), 7.32 (m, 2H, H^(Ar)) 7.18 (d, J=7.6Hz, 1H, H^(Ar)), 7.08 (m, 1H, H^(Ar)), 6.81 (t, J=8.1 Hz, 1H, H^(Ar)),4.96 (s, 2H, CH₂—O), 4.63 (s, 2H, CH₂—N), 3.97 (dqd, J=9.2, 7.0, 1.1 Hz,4H, CH₂—O—P), 3.13 (m, 2H, H², H⁶ pip), 3.06 (d, J=21.4 Hz, 2H, CH₂—P),2.67 (d, J=7.6 Hz, 2H, CH₂), 2.13 (m, 2H, H², H⁶ pip), 1.85 (bd, J=13.4Hz, 2H, H³, H⁵ pip), 1.75 (m, 1H, H⁴ pip), 1.44 (m, 2H, H³, H⁵ pip),1.12 (dt, J=7.3, 0.6 Hz, 6H, CH₃).

HRMS-ESI (m/z) [M+H]⁺ calculated for C₃₉H₄₄F₃N₃O₄P 706.3022, found706.3019.

Example 79: Synthesis of (E79)6-[[4-[[2-[[4-(diethoxyphosphorylmethyl)phenyl]-methoxy]phenyl]methyl]-1-piperidyl]methyl]-2-[4-(trifluoromethoxy)phenyl]-3a,7a-dihydro-1H-benzimidazole

Procedure:

The title compound (E79) was obtained following the general procedure 12from compound (38) (43 mg, 1 eq., 0.14 mmol), SOCl₂ (296 μL, 29 eq.,4.06 mmol), compound (51) (60 mg, 1 eq., 0.14 mmol), anddiisopropylethylamine (116 μL, 5.3 eq., 0.70 mmol) in acetonitrile (3mL). After purification by silica gel column chromatography, elutingdichloromethane/methanol 95:5, the title compound (E79) was obtained asan amorphous creamy solid (20 mg, 21%).

Characterization:

¹H NMR: (250 MHz, MeOD) δ 8.21 (d, J=9.3 Hz, 2H, H^(Ar)), 7.78 (s, 1H,H^(Ar)), 7.68 (s, 1H, H^(Ar)), 7.46 (d, J=8.7 Hz, 2H, H^(Ar)), 7.39 (s,1H, H^(Ar)), 7.32 (m, 4H, H^(Ar)), 7.11 (m, 2H, H^(Ar)) 6.97 (d, J=7.5Hz, 1H, H^(Ar)), 6.83 (td, J=7.1, 0.6 Hz, 1H, H^(Ar)), 5.05 (s, 2H,CH₂—O), 4.37 (s, 2H, CH₂—N), 3.99 (dqd, J=8.8, 7.1, 0.6 Hz, 4H,CH₂—O—P), 3.42 (m, 2H, H², H⁶ pip), 3.21 (d, J=21.1 Hz, 2H, CH₂—P), 2.94(bs, 2H, H², H⁶ pip), 2.61 (d, J=5.7 Hz, 2H, CH₂), 1.95 (m, 1H, H⁴ pip),1.82 (bd, J=15.8 Hz, 2H, H³, H⁵ pip), 1.53 (m, H³, H⁵ pip), 1.20 (dt,J=7.1, 0.5 Hz, 6H, CH₃).

HRMS-ESI (m/z) [M+H]⁺ calculated for C₃₉H₄₄F₃N₃O₅P 722.2971, found722.2966.

Example 80: Synthesis of (E80)6-[[4-[[2-[[4-(diethoxyphosphorylmethyl)phenyl]-methoxy]phenyl]methyl]-1-piperidyl]methyl]-2-[3-(trifluoromethoxy)phenyl]-1H-benzimidazole

Procedure:

The title compound (E80) was obtained following the general procedure 12from compound (40) (43 mg, 1 eq., 0.14 mmol), SOCl₂ (296 μL, 29 eq.,4.06 mmol), compound (51) (60 mg, 1 eq., 0.14 mmol), anddiisopropylethylamine (116 μL, 5.3 eq., 0.70 mmol) in acetonitrile (3mL). After purification by silica gel column chromatography, elutingdichloromethane/methanol 95:5, the clean compound (E80) was obtained asan amorphous creamy solid (16 mg, 17%).

Characterization:

¹H NMR: (400 MHz, MeOD) δ 8.11 (d, J=8.9 Hz, 1H, H^(Ar)), 8.04 (s, 1H,H^(Ar)), 7.66 (m, 3H, H^(Ar)), 7.45 (m, 2H, H^(Ar)), 7.32 (m, 2H,H^(Ar)), 7.21 (m, 2H, H^(Ar)), 7.09 (m, 2H, H^(Ar)), 6.91 (d, J=8.8 Hz,1H, H^(Ar)), 6.82 (t, J=7.6 Hz, 1H, H^(Ar)), 4.98 (s, 2H, CH₂—O), 4.63(s, 2H, CH₂—N), 3.92 (dqd, J=9.3, 7.2, 1.0 Hz, 4H, CH₂—O—P), 3.58 (m,2H, H², H⁶ pip), 3.07 (d, J=21.4 Hz, 2H, CH₂—P), 2.94 (bs, 2H, H², H⁶pip), 2.68 (d, J=5.8 Hz, 2H, CH₂), 2.09 (m, 2H, H², H⁶ pip), 1.82 (bd,J=13.4 Hz, 2H, H³, H⁵ pip), 1.74 (m, 1H, H⁴ pip), 1.6 (m, 2H, H³, H⁵pip), 1.13 (dt, J=7.0, 0.3 Hz, 6H, CH₃).

HRMS-ESI (m/z) [M+H]⁺ calculated for C₃₉H₄₄F₃N₃O₅P 722.2971, found722.2967.

Example 81: Antiviral Evaluation of the Synthesized Molecules

Some of the synthesized compounds were screened using a virus infectionassay following a published procedure (Lee, K.; Ren, T.; Côté, M.;Gholamreza, B.; Misasi, J.; Bruchez, A.; Cunningham, J., Inhibition ofEbola virus infection: Identification of Niemann-Pick C1 as the targetby optimization of a chemical probe. ACS Med. Chem. Lett. 2013, 4,239-243 (Supporting Information)).

Cell Culture, Virus Production and Measurement of Infection

Vero and 293T cells were cultured in DMEM (Invitrogen) supplemented withpenicillin/streptomycin (1000 U/ml), L-glutamine (2 mM, Invitrogen), FBS(5%) and FetalPlex (5%, Gemini).

CHO_(null) (Chinese hamster ovary fibroblasts lacking NPC1) andCHO_(NPC1) (Chinese hamster ovary fibroblasts expressing NPC1) cellswere cultured in equal mixture of F12 and DMEM media (Invitrogen) withpenicillin/streptomycin, L-glutamine (Invitrogen) and FBS.

Ectodomain of Ebola Virus glycoprotein (EboV GP) was produced in 293Tcells.

Vesicular stomatitis virus (VSV) particles encoding luciferase andpseudotyped with EboV GP, Lassa fever virus GP or VSV GP were producedin 293T cells.

Virus infection assays were performed in 384-well plate format usingluciferase reporter.

Vesicular Stomatitis Virus (VSV) pseudotyped viruses expressing GreenFluorescent Protein (GFP), which are replicon models of EBoV, were addedto cells in serial 10-fold dilutions and assayed using fluorescencemicroscopy.

An infectious unit (i.u.) was defined as one GFP-expressing cell withina range where the change in GFP-positive cells is directly proportionalto the virus dilution.

For VSV expressing the luciferase reporter, pseudotyped virus was addedto cells and luciferase activity was assayed during 6 to 20 hourspost-infection using the firefly luciferase kit (Promega).

Signal was measured in relative luminescence units (RLU) using anEnVison plate reader (Perkin Elmer).

In experiments involving inhibitors, stock solutions of 20 mM or 10 mMin DMSO were diluted to obtain a final concentration of 1% DMSO inmedia.

Inhibitory activity was stable in the media of cultured cells for morethan 72 hours as assessed using a single cycle entry assay.

Infection of target cells with LacZ-encoding retroviral pseudotypes wasperformed in the presence of 5 μg/ml polybrene (Sigma).

72 hours post-infection, cells were stained for LacZ activity and titerwas determined by counting positive foci and expressed as focus formingunits (FFU) per ml of virus.

Two different concentrations of compounds were evaluated, 2 and 10 μM.In the table are presented results for the compounds which have beenevaluated.

Inhibition (%) Compound 10 μM 2 μM (E11) 95 (E14) 80 (E15) 93.5 2 (E16)91.6 64.1 (E17) <20 (E18) <20 (E19) <20 (E20) <20 (E22) 80 <20 (E29) 80<20 (E52) 82.9 64.3 (E57) <20 (E58) 98 (E59) <20 (E60) 98

The compounds evaluated for their Ebola virus inhibition show goodresults. Indeed, some compounds evaluated can inhibit Ebola virus withan inhibition rate higher than 80% and some of them, higher than 95%.Even the compounds less active, they show an inhibition rate (with acompound concentration of 10 μM) of about 20%. This inhibition rateshows that all the compounds evaluated show a Ebola virus inhibitionactivity.

The invention claimed is:
 1. A compound of formula (I):

wherein: X represents: a C═O group; an alkyl group, linear or branched,comprising 1 to 6 carbon atoms; or a group of formula —NR—(C₁-C₆)alkyl-,the alkyl being linear or branched; Y represents CH or nitrogen atom; R¹represents: an aryl group, comprising 6 to 10 carbon atoms,non-substituted or substituted by at least one group selected from thegroup consisting of: haloalkyl, haloalkoxyl, and an alkyl or alkoxylgroup, the alkyl being linear or branched, and comprising 1 to 6 carbonatoms; an heteroaryl group, comprising 6 to 10 members, non-substitutedor substituted by at least one group selected from the group consistingof: haloalkyl, haloalkoxyl, and an alkyl or alkoxyl group, the alkylbeing linear or branched, and comprising 1 to 6 carbon atoms; aCH-(aryl)₂ group, the aryl comprising 6 to 10 carbon atoms,non-substituted or substituted by at least one group selected from thegroup consisting of: haloalkyl, haloalkoxyl, and an alkyl or alkoxylgroup, the alkyl being linear or branched, and comprising 1 to 6 carbonatoms; or a CH-(heteroaryl)₂ group, the heteroaryl comprising 6 to 10members, non-substituted or substituted by at least one group selectedfrom the group consisting of: haloalkyl, haloalkoxyl, alkyl or alkoxylgroup, the alkyl being linear or branched, and comprising 1 to 6 carbonatoms; R² represents: a (C₁-C₆)alkyl-aryl-R³ group, the aryl comprising6 to 10 carbon atoms and the alkyl being linear or branched; aC(O)N(R)-aryl-R⁵ group, the aryl comprising between 6 to 10 carbonatoms; a C(O)—(C₁-C₆)alkyl-O-aryl-Hal group, with Hal represents anhalogen, the aryl comprising between 6 and 10 carbon atoms and the alkylbeing linear or branched; a C(O)O—(C₁-C₆)alkyl-aryl group, the arylcomprising between 6 to 10 carbon atoms and the alkyl being linear orbranched; or a O-aryl-IV group, the aryl comprising between 6 to 10carbon atoms; R³ represents a OR⁴ group, haloalkyl or haloalkoxyl,wherein the alkyl is linear or branched, and comprises 1 to 6 carbonatoms; R⁴ represents a (C₁-C₆)alkyl-aryl-COOR group, a haloalkyl groupor a (C₁-C₆)alkyl-aryl-(C₁-C₆)alkyl-PO(OR)₂ group, wherein alkyl islinear or branched and comprises 1 to 6 carbon atoms and the arylcomprises between 6 and 10 carbon atoms; R⁵ represents an alkyl group,linear or branched, comprising 1 to 6 carbon atoms; or a haloalkyl,linear or branched, comprising 1 to 6 carbon atoms; R represents analkyl group, linear or branched, comprising 1 to 6 carbon atoms, or ahydrogen atom; or their pharmaceutically acceptable salts, hydrates,solvates, esters or their optical isomers, racemates, diastereoisomers,enantiomers, tautomers, or a mixture thereof.
 2. The compound accordingto claim 1 for which R¹ is selected from the group consisting of: aphenyl group, non-substituted or substituted by at least one groupselected from the group consisting of: haloalkyl, haloalkoxyl, alkyl oralkoxyl group, the alkyl being linear or branched, and comprising 1 to 6carbon atoms; a pyridine group non-substituted or substituted by atleast one group selected from the group consisting of: haloalkyl,haloalkoxyl, alkyl or alkoxyl group, the alkyl being linear or branched,and comprising 1 to 6 carbon atoms; a pyrimidine group, non-substitutedor substituted by at least one group selected from the group consistingof: haloalkyl, haloalkoxyl, alkyl or alkoxyl group, the alkyl beinglinear or branched, and comprising 1 to 6 carbon atoms; and a benzhydrylgroup non-substituted or substituted by at least one group selected fromthe group consisting of: haloalkyl, haloalkoxyl, alkyl or alkoxyl group,the alkyl being linear or branched, and comprising 1 to 6 carbon atoms.3. The compound according to claim 1 for which R′ is selected from thegroup consisting of: a phenyl group non-substituted or substituted by atleast one group selected from the group consisting of: fluoroalkyl,fluoroalkoxyl, alkyl or alkoxyl group, the alkyl being linear orbranched, and comprising 1 to 6 carbon atoms; a pyridine groupnon-substituted or substituted by at least one group selected from thegroup consisting of: haloalkyl, haloalkoxyl, alkyl or alkoxyl group, thealkyl being linear or branched, and comprising 1 to 6 carbon atoms; anda benzhydryl group non-substituted or substituted by at least one groupselected from the group consisting of: fluoroalkyl, fluoroalkoxyl, alkylor alkoxyl group, the alkyl being linear or branched, and comprising 1to 6 carbon atoms.
 4. The compound according to claim 1 for which Xrepresents: a (C═O) group; or an alkyl group, linear or branched,comprising 1 to 3 carbon atoms.
 5. The compound according to claim 1 forwhich Y represents a CH group.
 6. The compound according to claim 1 forwhich Y represents a nitrogen atom.
 7. A pharmaceutical compositioncomprising at least one compound of formula (I) according to claim 1 asactive principle, and optionally a pharmaceutically acceptableexcipient.
 8. A method of treating a viral disease comprisingadministering to a patient in need thereof an effective amount of thecompound of formula (I) according to claim
 1. 9. A method of treating afilovirus infection comprising administering to a patient in needthereof an effective amount of the compound according to claim
 1. 10. Amethod of treating an Ebola virus infection comprising administering toa patient in need thereof an effective amount of the compound accordingto claim
 1. 11. A method of treating a retrovirus infection comprisingadministering to a patient in need thereof an effective amount of thecompound according to claim
 1. 12. A method of treating a HumanImmunodeficiency Virus (HIV) infection comprising administering to apatient in need thereof an effective amount of the compound according toclaim
 1. 13. A method of treating a pathology selected from the groupconsisting of a cholesterol disorder, a metabolic disorder, obesity,AIDS, congenital disease, genetic disease, and Niemann-Pick disease typeC1 comprising administering to a patient in need thereof an effectiveamount of the compound according to claim
 1. 14. A method of treating aviral disease comprising administering to a patient in need thereof aneffective amount of the pharmaceutical composition according to claim 7.15. A method of treating a filovirus infection comprising administeringto a patient in need thereof an effective amount of the pharmaceuticalcomposition according to claim
 7. 16. A method of treating an Ebolavirus infection comprising administering to a patient in need thereof aneffective amount of the pharmaceutical composition according to claim 7.17. A method of treating a retrovirus infection comprising administeringto a patient in need thereof an effective amount of the pharmaceuticalcomposition according to claim
 7. 18. A method of treating a HumanImmunodeficiency Virus (HIV) infection comprising administering to apatient in need thereof an effective amount of the pharmaceuticalcomposition according to claim
 7. 19. A method of treating a pathologyselected from the group consisting of a cholesterol disorder, ametabolic disorder, obesity, AIDS, congenital disease, genetic disease,and Niemann-Pick disease type C1 comprising administering to a patientin need thereof an effective amount of the pharmaceutical compositionaccording to claim 7.